Review

Advances on Bioactive Metabolites with Potential for the

Biocontrol of Plant Pathogenic Bacteria †
Pierluigi Reveglia 1 , Gaetano Corso 1 and Antonio Evidente 2, *

1 Department of Clinical and Experimental Medicine, University of Foggia, Viale Pinto 1, 71121 Foggia, Italy;
pierluigi.reveglia@unifg.it (P.R.); gaetano.corso@unifg.it (G.C.)
2 Institute of Biomoleular Chemistry National Research Council, Via Campi Flegrei 34, 80078 Pozzuoli, Italy
* Correspondence: evidente@unina.it
† Dedicated to Giuseppe Surico, emeritus professor of the University of Florence, Italy, on the occasion of his
eightieth birthday. Prof. Surico is a world leader in Plant Pathology and multidisciplinary research carried out
on phytotoxins in strictly collaboration with chemists of natural substances.

Abstract: The increase in the world population, which will be almost 10 billion by 2050, will require
considerable efforts to significantly increase food production. Despite the considerable progress
made in agriculture, this need is becoming an emergency due to desertification, environmental
pollution and climate changes. Biotic stresses, such as pathogenic bacteria and fungi, primarily
contribute to significant losses in agricultural productivity and compromise food safety. These
harmful agents are predominantly managed using large quantities of synthetic pesticides. However,
this widespread use has led to substantial environmental pollution, increased pest resistance and
toxic residues in agricultural produce, which subsequently enter the food supply, posing severe
health risks to humans and animals. These challenges have significantly driven the advancement of
integrated pest management strategies to reduce or eliminate synthetic pesticides. A practical and
viable alternative lies in biopesticides—methods developed from natural products that are safe for
human and animal health. This approach aligns with the strong demand from consumers and public
authorities for safer pest control solutions. This review was focused on the isolation, chemical and
biological characterization of natural products for the biocontrol of phytopathogenic bacteria and, in
some cases, fungi with potential eco-friendly applications.
Citation: Reveglia, P.; Corso, G.;
Evidente, A. Advances on Bioactive
Keywords: plant pathogens; bacteria; biocontrol; natural substances
Metabolites with Potential for the
Biocontrol of Plant Pathogenic
Bacteria. Pathogens 2024, 13, 1000.
https://doi.org/10.3390/
pathogens13111000 1. Introduction
Phytopathogenic bacteria and fungi produce different phytotoxins that are involved
Academic Editors: Hernan
Garcia-Ruiz and Nikolaos Skandalis
in heavy diseases that seriously damage agrarian, forest and ornamental plants [1–3]. Sev-
eral studies have been carried out on the role of bioactive microbial metabolites in the
Received: 4 October 2024 pathogenic process and on their potential application in agriculture [4–8]. These studies
Revised: 7 November 2024 have allowed the scientists to identify substances which are not only essential for agricul-
Accepted: 13 November 2024 ture but also have potential applications in other fields. Microbial bioactive metabolites,
Published: 15 November 2024
including phytohormones, phytoalexins, antibiotics, fungicides, herbicides and elicitors,
belong to several classes of natural compounds of low molecular weight (amino acids,
aromatic compounds, anthraquinone, naphthoquinone, terpenes, macrolides, furanones,
Copyright: © 2024 by the authors.
cytokinins, auxins, etc.) as well as high molecular weight (proteins, glycoproteins and more
Licensee MDPI, Basel, Switzerland. recently polysaccharides) [1,2,9–12]. One of the main applications of bioactive microbial
This article is an open access article metabolites is to control weed and parasitic plant diffusion, which are a severe problem for
distributed under the terms and crops and pastures, as well as for forest heritage and ornamental plants [11,13,14]. Today,
conditions of the Creative Commons the control of pests is reached via the extensive use of chemicals; pesticides, which, when
Attribution (CC BY) license (https:// applied several times, cause an increase in pest resistance in hosts; high environmental
creativecommons.org/licenses/by/ pollution and serious problems to human and animal health [15,16]. Despite the significant
4.0/). rise in pesticide usage, crop losses have remained relatively high over the past 40 years.

Pathogens 2024, 13, 1000. https://doi.org/10.3390/pathogens13111000 https://www.mdpi.com/journal/pathogens

Pathogens 2024, 13, 1000 2 of 19

This approach has yet to enable farmers to adapt production systems or effectively in-
crease crop productivity, often resulting in greater vulnerability to pest damage [17]. In
contrast, employing biological control agents—such as specific insects and bacterial or
fungal pathogens—alongside natural phytotoxins offers an environmentally compatible,
highly targeted and sustainable long-term solution. Some reviews concerning these aspects
have been published [11,14,18,19].
Metabolites from different natural sources, with potential activity against bacteria
inducing severe diseases to agrarian and forest plants, are considered an important group
of new potential bactericides. Thus, some reviews have treated natural bactericides but
only partially dealing with this argument. Among them, there is a review dealing with
the metabolites produced by genus Xylaria Hill (e.g., Schrank, 1789, Xylariaceae), which
includes various endophytic fungi species. Certain fungi produce a variety of natural
compounds with potential applications such as herbicides, fungicides and insecticides;
others demonstrate antibacterial, antimalarial, antifungal and α-glucosidase inhibitory
activities, showing promise for use in both agriculture and medicine [20]. Another study
focused on bacteriocins, antimicrobial substances produced by many bacteria, including
lactic acid bacteria (LAB), which are effective against various saprophytic and pathogenic
microorganisms. This review emphasized the role of immobilized bacteriocins from LAB,
highlighting their significance in natural food preservation and shelf-life extension, their
use in health care for creating probiotic foods and beverages, their potential as antibiotic
alternatives in clinical settings and their application as biocontrol agents against plant
pathogens in agriculture [21]. Another review treated bioactive metabolites, and, in partic-
ular, pantocin A produced by Pantoea species, which was evaluated as a biocontrol agent
for fire blight disease of apple and pear [22]. Surprisingly, seaweeds also are a source
of bioactive compounds, already used in different industries and with antibiotic activity
against several phytopathogens agents. Among these compounds, some are identified for
their eliciting ability to trigger a priming defense mechanism [23]. Successively, a review
discussed cyanobacteria as organisms with significant potential in agriculture as biopesti-
cides. In fact, they produce different biological active compounds that have a demonstrated
efficacy as antibacterial, antiviral, antifungal, insecticidal, herbicidal and more [24].
Considering the serious diseases induced by phytopathogenic bacteria and their
consequent heavy economic losses, in the present review, the natural compounds with an-
tibacterial activity obtained from different sources (bacteria, fungi and plants) are reported.
In particular, the treatment was focused on their chemical and biological properties and on
their potential application as bacteriocides in agriculture. The results discussed in the three
different sections were obtained from Sci-Finder research and chronologically reported.
The results of the SARs (structure–activity relationships) studies, as well as the mode of
action of some specialized metabolites and their efficacy against severe and specific plant
diseases, have also been discussed.

2. Bactericides from Bacteria

Pseudomonas savastanoi pv. savastanoi (Ps. savastanoi), is a very harmful phytopathogen
bacterium and is a common resident in the olive phyllosphere. This bacterium invades the
host tissues by penetrating through wounds of various natures, inducing the formation
of nodes. The virulence factors produced by the bacterium, including indole-3-acetic acid
(IAA) [25], various cytokinins [26] and hrp genes [27], play a fundamental role in the
process of node differentiation. The Pseudomonas syringae pv. ciccaronei strain NCPPB2355
produced a bacteriocin capable of inhibiting the growth of the Ps. savastanoi strain. The
bacteriocin was characterized as a protein that was revealed in the three SDS (sodium
dodecyl sulfate)-PAGE bands with molecular weights of 76, 63 and 45 kDa (kDalton),
respectively, and that was resistant to non-polar organic solvents and active under neutral
conditions [28]. Subsequently, this bacteriocin was tested at different levels of purification
and concentrations in culture and in plants, showing a significant inhibition of the mul-
tiplication of Ps. savastanoi. The bacteriocin treatments inhibited the formation of olive
Pathogens 2024, 13, 1000 3 of 19

nodes in the plant induced by different Ps. savastanoi strains. The same bacteriocin was
also effective in controlling the multiplication of epiphytic pathogen populations, as the
bacterial populations recovered after 30 days were at least 350 and 20 times lower than the
control populations on twigs and leaves, respectively [29].
Tolaasin I, tolaasin II and five additional minor analogs—designated as tolaasins
A, B, C, D and E (compounds 1–7, Figure 1, Table 1)—are part of the lipodepsipeptide
(LPD) group [30] and are produced by Pseudomonas tolaasii, the pathogen responsible for
brown blotch disease in Agaricus bisporus as well as the yellowing of Pleurotus ostreatus.
The antimicrobial effects of tolaasins (3–7) were evaluated alongside tolaasin I and II (1
and 2) against several organisms: the yeast Rhodotorula pilimanae, the fungus Rhizoctonia
solani, Gram-positive bacteria like Bacillus megaterium and Rhodococcus fascians and Gram-
negative bacteria like Escherichia coli and Erwinia carotovora subsp. carotovora. The results
indicated that B. megaterium and R. fascians were the most sensitive microorganisms as,
except for tolaasin C, all the LPDs tested inhibited the growth of these bacteria, but the
differences among their specific activities were observed. Tolaasin D (6) was the most potent
compound, followed by tolaasin I and II (1 and 2), with minimal inhibitory quantities of
0.16, 0.32 and 0.64 µg, respectively. In contrast, tolaasins A, B and E (3, 4 and 7) exhibited
lower activity, with minimal inhibitory quantities of 1.28 and 2.56 µg, respectively. The
fungus R.nia solani showed a similar sensitivity to these compounds. None of the LPDs
inhibited the growth of Gram-negative bacteria, such as E. coli and E. carotovora subsp.
carotovora at the concentrations tested. However, tolaasins I, II and D (1, 2 and 6) effectively
inhibited the growth of R. pilimanae [31].
Considering the results of SAR studies, the lactone ring and the N-terminus acyl
moiety appeared to be important to impart the antimicrobial activity of tolaasins compared
to tolaasin I (1) and tolaasin A (3), which contain pentanedioic acid instead of β-hydroxy
octanoic acid, demonstrating reduced activity, while tolaasin C (5), the linear form of 1
that lacks the lactone ring, shows no activity. Additionally, the substituent at position
C-15 plays a significant role in inhibitory activity. Specifically, replacing isoleucine at
position 15 with valine or leucine, as seen in tolaasins B and D (4 and 6), led to a decrease
or increase in antimicrobial activity relative to compound 1. Furthermore, leucine at
position 15, as in tolaasin E (7), reduced activity compared to compound 2. Although
this effect appears contradictory when comparing tolaasin D (6), compound 2 differed
from 1 due to the substitution of homoserine with glycine at position 16 [31]. The LPD,
defined as the L-Inducing Principle (WLIP, 8, Figure 1, Table 1), produced by Pseudomonas
reactans NCPPB1311, is known as an inductor in the “white line” assay for the specific
identification of P. tolaasii [32]. WLIP (8) should be regarded as an actual toxin, as it
inhibits the growth of fungi—including cultivated mushrooms such as Agaricus bisporus,
Lentinus edodes and Pleurotus species—as well as Chromista and Gram-positive bacteria.
Additionally, compound 8 inhibited the growth of B. megaterium ITM100 with a minimal
inhibitory quantity (MIQ) of 0.32 µg and that of fungi, Chromista and Gram-positive
bacteria at M.I.Q. values higher than those of tolaasin I (1). LPD 8 did not inhibit the
growth of most of the tested Gram-negative bacteria, with the only exception of the strain E.
carotovora subsp. carotovora. When tested against blocks of Agaricus bisporus and compared
to LPD 1, WLIP demonstrated lower activity in altering the mushroom’s pseudo-tissues.
Both WLIP and tolaasin I were shown to cause red blood cell lysis through colloid–osmotic
shock, mediated by the formation of transmembrane pores; however, WLIP exhibited
greater hemolytic activity than tolaasin I. The antifungal properties of WLIP, along with
the observation that a virulent morphological variant of P. reactans lacks WLIP production,
suggest that WLIP may play a key role in the interactions between P. reactans and cultivated
mushrooms [33].
Pathogens 2024,
Pathogens 13,13,
2024, 1000
x FOR PEER REVIEW 4 4ofof20
19

Figure 1. Cont.
 Pathogens
Pathogens 2024,13,
2024, 13,1000
x FOR PEER REVIEW 5 of
5 of2019

Figure 1. Bacterial metabolites with potential for the biocontrol of plant pathogenic bacteria.
Figure 1. Bacterial metabolites with potential for the biocontrol of plant pathogenic bacteria.

Theantimicrobial
The antimicrobial activities
activities ofof five
five lipodepsipeptides
lipodepsipeptides(1, (1,2,2,66and
and7);
7);ofofthe
theWLIP
WLIP(8) (8)
of the two tolaasin I (1) derivatives, hexaacetyl and the tetrahydro-tolaasin I (9and
of the two tolaasin I (1) derivatives, hexaacetyl and the tetrahydro-tolaasin I (9 and10,10,
Figure1,1,Table
Figure Table 1)
1) and
and of of the
the methyl
methyl ester
ester of
of the
the WLIP
WLIP (11,(11, Figure
Figure 1) 1) were
weretested
testedagainst
against
several bacteria and fungi pathogenic of agrarian plants. In the
several bacteria and fungi pathogenic of agrarian plants. In the same experiment, four same experiment, four
2,5-
2,5-diketopiperazines
diketopiperazines (12,1413,
(12, 13, and1415,
andFigure
15, Figure 1, Table
1, Table 1) were1) tested.
were tested. Diketopiperazine
Diketopiperazine (DKP),
(DKP), represents
represents the smallestthe knownsmallest
class ofknown class of[34].
cyclic peptides cyclic
Among peptides [34]. Among
2,5-diketopiperazines,
2,5-diketopiperazines,
the most known is maculosin-1 the most(cyclo(L-Pro-L-Tyr))
known is maculosin-1 (12),(cyclo(L-Pro-L-Tyr))
which is a host specific (12),phytotoxin
which is
a host specific phytotoxin produced by Alternaria alternata, a pathogen
produced by Alternaria alternata, a pathogen of knapweed [35]. DKP 12 was also recently of knapweed [35].
DKP 12 was also recently isolated from Lysobacter capsici AZ78 and
isolated from Lysobacter capsici AZ78 and showed antifungal activity against Phytophthora showed antifungal
activity and
infestans against Phytophthora
Plasmopara infestans
viticola, and Plasmopara
both causal viticola, both
agents of important crop causal agents
diseases [36].ofLPDs
im-
portant crop diseases [36]. LPDs and DKPs were assayed towards
and DKPs were assayed towards bacteria belonging to the Pseudomonas genus and the bacteria belonging to
the Pseudomonas genus and the
pathogens of important agrarian plants. pathogens of important agrarian plants.
These bacteria
These bacteria include
include the thefollowing:
following:Burkholderia
Burkholderia caryophylli
caryophylli (syn. Pseudomonas
(syn. Pseudomonascar-
yophylli), which
caryophylli), is the
which causal
is the agent
causal for bacterial
agent wilt ofwilt
for bacterial carnation [37]; P.[37];
of carnation syringae pv. panici,
P. syringae pv.
which is a worldwide diffused pathogen of crops [38,39]; Pseudomonas
panici, which is a worldwide diffused pathogen of crops [38,39]; Pseudomonas syringae pv. syringae pv. tabaci,
Pathogens 2024, 13, 1000 6 of 19

tabaci, which induces brown spots on tobacco [40]; P. syringae pv. siringae, which is the most
polyphagous bacterium in the P. syringae complex due to its wide host range, first affecting
woody and herbaceous host plants [41] and Pseudomonas syringae pv. japonica, which causes
the black node disease of barley (Hordeum vulgare L.) and wheat (Triticum aestivum L.) [42].
B. subtilis, B. megaterium and E. coli, which are laboratory strains, were also used. The
test results showed that among the tolaasins and their two derivatives, the LPDs 1, 2 and
6 and the tetrahydrotolaasin I (10) inhibited all the bacteria (MIC (minimum inhibition
concentration) range of 0.1–0.9 µg/mL), while tolaasin E and hexacetyltolaasin I (7 and 16)
showed a MIC in the range of 3–6 and 0.7–1 µg/mL, respectively. E. coli growth was not
inhibited. The highest antimicrobial activity was exhibited by tolaasin D (6) (MIC range
of 0.1−0.2 µg/mL) and the lesser toxicity was shown by tolaasin E (7) and the derivatives
9 and 10 (MIC range of 0.7–1.0 and 0.2–3.0 µg/mL). The amino acid residue at the C-16
position of the macrolactone ring seemed not to be important for the activity as LPDs 1 and
2 showed strong bactericidal activity. This SAR relation, as well as the others described
above were confirmed. Furthermore, the acetylation of the hydroxyl groups of macrocyclic
lactones and the hydrogenation of two residues of 2-butenylbutiric acids present in the
derivatives 9 and 10, significantly induced a decrease in the activity. The lack of toxicity of
the WLIP (8) and its methyl ester (11) against all the phytopathogenic bacteria was probably
due to strong structural differences with tolaasins. However, LPD 8 exhibited activity
against the two laboratory Gram-positive strains B. subtilis and B. megaterium, except in
compound 12 on E. coli, the results of the bioassays of the four DKPs (12–15) showed that
almost all the dicyclopeptides had bactericidal activity against all the bacteria used. The
2,5-diketopiperazine compound 13 was not toxic. Among the active diketopiperazines
(DKPs) 12, 14 and 15, the highest antimicrobial activity was observed in cyclo(L-Pro-L-Tyr),
12, with a minimum inhibitory concentration (MIC) range of 15–20 µg/mL, while the other
two compounds (14 and 15) exhibited lower activity, with MIC ranges of 500–800 µg/mL.
The configuration of the amino acids, whether D or L, played a crucial role in determining
activity. This was evident from the inactivity of compound 13 and the reduced activity
of DKP 15, which differed from 12 only by the opposite D stereochemistry of the proline
residue, resulting in a 50–60 times decrease in activity compared to 12. The noteworthy
reduction in activity by 40–50 times showed by compound 14, in respect to that of 12, which
differs for the substitution of L-Tyr with L-Leu, demonstrated that the nature of the amino
acids, which constitute dicyclopeptides, also affected the activity [43].
Entomopathogenic bacteria (EPB) produce antibiotics that are effective against the
fire blight bacterium Erwinia amylovora, including strains resistant to streptomycin, and
demonstrate similar efficacy in phytotron experiments as kasugamycin or streptomycin.
Among these EPB strains, Xenorhabdus budapestensis and Xenorhabdus szentirmaii produced
antibiotics that inhibited colony formation and mycelial growth of Phytophthora nicotianae.
Bicornutins A-C were isolated from X. budapestensis (16, Figure 1, Table 1) and were identi-
fied as new hexapeptides. While bicornutins B and C share similarities with bicornutin A,
their exact structures have yet to be reported. Though in unknown ratios, ten preparations
containing all three bicornutin compounds exhibited antibacterial activity against B. subtilis,
with inhibition zones ranging from 13 to 24 mm. The same bicorbutin complex was also
tested against E. amylovora at four concentrations and the bacterium appeared to be very
susceptible to each of all the concentrations assayed [44].
L-Furanomycin [(2S,2′ R,5′ S)-2-amino-2-(5′ methyl-2′ ,5′ -dihydrofuran-2′ -yl)]acetic acid
(17, Figure 1, Table 1), a non-proteinogenic amino acid, was produced by Pseudomonas
fluorescens SW25, a strain originally isolated from wheat rhizosphere [45]. Genetic studies
demonstrate that the P. fluorescences SW25 is the closest strain to WH6, which produces
another non-proteinogenic amino acid identified as 4-formylaminooxyvinylglycine (L-
2-amino-4-formylaminooxy-trans-3-butenoic acid, FVG, 18, Figure 1, Table 1). FVG (18)
showed selective herbicidal and antimicrobial activities and irreversibly arrested the germi-
nation of a large number of graminaceous species, including a number of invasive grassy
weeds [46]. Furthermore, compound 18 exhibited selective antimicrobial activity against
Pathogens 2024, 13, 1000 7 of 19

some bacteria including E. amylovora, the causal agent of the disease of orchard crops known
as fire blight [47]. The P. fluorescence strain SW25 produced, together with compound 17 and
other non-proteinogenic amino acids such as FVG (18), while rhizobitoxine (4-(2-amino-3-
hydroxypropoxy)vinylglycine, methoxyvinylglycine (MVG), L-2-amino-4-methoxy-trans-
3-butenoic acid and 3-methylarginine were produced by Pseudomonas. andropogonis [48],
Pseudomonas aeruginosa (ATCC-7700) [49] and Pseudomonas syringae pv. syringae [50], re-
spectively. L-Furanomycin (17) inhibited the growth of several microorganisms as Shigella
paradysenteriae, Salmonella paratyphi A and B- subtilis [51]. Other bacteria are susceptible
to furanomycin, including several plant pathogens as Dickeya dadantii, P. syringae and E.
amylovora, as well as the nonpathogenic strain of B. megaterium [45].
Erucamide, behenic, palmitic, phenylacetic acids and β-sitosterol (19–23, Figure 1,
Table 1), were purified from the organic extract of B. megaterium and their activity was
tested against Agrobacterium tumefaciens T-37, E. carotovora EC-1 and Ralstonia solanacearum
RS-2. Palmitic acid (21) had no antibacterial activity (>500 µg/mL), while erucamide (19)
showed moderate antibacterial activity (MIC 500 µg/mL). Behenic acid (20) was active
with MICs of 250 µg/mL against T-37 and RS-2 strains while β-sitosterol (23) showed
significant activity against RS-2. (MIC of 15.6 µg/mL). Phenylacetic acid (22) exhibited
activity towards all the three strains T-37 and against EC-1 and RS-2 (with a MIC of 62.5,
125, 15.6 µg/mL, respectively) and showed potential for their biocontrol [52].
Guvermectin (GV, 24, Figure 1, Table 1), is a N9 –glucoside cytokinin derivative ob-
tained from the purification of Streptomyces sanjiangensis NEAU6 extract (Liu et al., 2022 [53].
To evaluate the antibacterial activity of GV and its mechanism targeting GMPs (Guanosine
5′ -monophosphate synthetase), an enzyme essential for bacterial guanine synthesis, various
biochemical and genetic methods were employed, including enzyme activity assays, site-
directed mutagenesis, bio-layer interferometry and molecular docking assays. The target
bacteria included R. solanacearum, which affects many host plants, Pseudomonas syringae pv.
actinidiae, the pathogen responsible for kiwifruit canker and Xanthomonas oryzae pv. oryzae,
which causes significant yield reductions in rice (10–50%). The results indicated that GV
effectively inhibits GMPs, disrupting bacterial guanine synthesis, thereby shedding light on
the antibacterial mechanism of GV and its potential as a biocontrol agent in agriculture [54].
Pantocins A and B (25 and 26, Figure 1, Table 1), two peptides, were isolated from
an endophytic strain, Pantoea PC-2B, derived from Convolvulus arvensis L., a prevalent
weed in potato fields. The antagonistic activity of pantocins A and B was tested against
Pectobacterium carotovorum subsp. carotovorum (Pcc), the pathogen responsible for potato
tuber decay, resulting in an approximately 58.8% reduction in tuber decay in vivo. When the
Pantoea strain was used for pre-treatment, it led to a 56.7% reduction in disease incidence
and a 52% reduction in curative challenges during semi-practical storage trials. These
findings suggest that the tested Pantoea strain may be a promising candidate for protecting
potato tubers from soft rot disease caused by Pcc [55].

Table 1. Bacterial metabolites with potential for the biocontrol of plant pathogenic bacteria.

Compounds Source Bacterium Target References

Pseudomonas syringae pv.
Bacteriocin Pseudomonas savastanoi pv. savastanoi [28,29]
ciccaronei
Bacillus megaterium and Rodococcus fascians [31]
Burkholderia caryophylli, P. syringae pv. panici, Pseudomonas
Tolaasin I (1), Table 1 Pseudomonas tolaasii
syringae pv. tabaci, P. syringae pv. siringae and Pseudomonas [43]
syringae pv. japonica, B. subtilis, Bacillus megaterium
Bacillus megaterium and Rodococcus fascians [31]

′′ Burkholderia caryophylli, P. syringae pv. panici, Pseudomonas

Tolaasin II (2)
syringae pv. tabaci, P. syringae pv. siringae and Pseudomonas [43]
syringae pv. japonica, B. subtilis, Bacillus megaterium
Pathogens 2024, 13, 1000 8 of 19

Table 1. Cont.

Compounds Source Bacterium Target References

Tolaasins A (3) ′′ Bacillus megaterium and Rodococcus fascians [31]
Tolaasins B (4) ′′ ′′ ′′

Tolaasins C (5) ′′ ′′ ′′

Bacillus megaterium and Rodococcus fascians [31]

′′ Burkholderia caryophylli, P. syringae pv. panici, Pseudomonas

Tolaasins D (6)
syringae pv. tabaci, P. syringae pv. siringae and Pseudomonas [43]
syringae pv. japonica, B. subtilis, Bacillus megaterium
Bacillus megaterium and Rodococcus fascian [31]

′′ Burkholderia caryophylli, P. syringae pv. panici, Pseudomonas

Tolaasins E (7)
syringae pv. tabaci, P. syringae pv. siringae and Pseudomonas [43]
syringae pv. japonica
B. megaterium, Erwinia carotovora subsp. carotovora [33]
WLIP (8) Pseudomonas reactans
B. subtilis and B. megaterium [43]
Burkholderia caryophylli, P. syringae pv. panici, Pseudomonas
Hexacetyltolaasin I (9) syringae pv. tabaci, P. syringae pv. siringae and Pseudomonas [43]
syringae pv. japonica,
Burkholderia caryophylli, P. syringae pv. panici, Pseudomonas
Tetrahydrotolaasin I (10) syringae pv. tabaci, P. syringae pv. siringae and Pseudomonas [43]
syringae pv. japonica, B. subtilis, Bacillus megateriums
WLIP methyl ester (11) B. subtilis and B. megaterium ′′

Burkholderia caryophylli, P. syringae pv. panici, Pseudomonas

Maculosin-1, ′′
Lysobacter capsici syringae pv. tabaci, P. syringae pv. siringae and Pseudomonas
Cyclo(L-Pro-L-Tyr) (12)
syringae pv. japonica, B. subtilis, Bacillus megaterium
Cyclo(L-Pro-L-Val) (13) ′′ Not toxic ′′

Burkholderia caryophylli, P. syringae pv. panici, Pseudomonas

Cyclo(L-pro-Leu) (14) ′′ syringae pv. tabaci, P. syringae pv. siringae and Pseudomonas ′′
syringae pv. japonica, B. subtilis, Bacillus megaterium, E.coli
Cyclo(D-Pro-L-Tyr) (15) ′′ ′′ ′′

Xenorhabdus
Bicornutin A (16) budapestensis and X. Erwinia amylovora [44]
szentirmaii
Pseudomonas fluorescens
L-Furanomycin (17) Dickeya dadantii, P. syringae, E. amylovora and b. subtilis [45]
SW25
4-Formylaminooxyvinyl Pseudomonas fluorescens
Erwinia amylovora [46,47]
glycine (18) WH6
Agrobacterium tumefaciens, Erwinia carotovora and Ralstonia
Erucamide (19) Bacillus megaterium [52]
solanacearum
Behenic acid (20) ′′ ′′ ′′

Palmitic acid (21) ′′ Not toxic ′′

Phenylacetic acid (22) ′′ ′′ ′′

β-Sitosterol (23) ′′ ′′ ′′

Ralstonia solanacearum, Pseudomonas syringae pv. actinidiae

Guvermectin (24) [54]
Xanthomonas oryzae pv. oryzae
Pantocin A (25) Pantoea sp. Pectobacterium carotovorum subsp. carotovorum [55]
Pantocin B (26) ′′ ′′ ′′

′′ means the same content.

 Pathogens 2024, 13, x FOR PEER REVIEW 10 of 20

Pathogens 2024, 13, 1000 9 of 19

3. Bacteriocides from Fungi

Papyracillic from
3. Bacteriocides acid (PA,
Fungi27, Figure 2, Table 2), a spiran complex toxin, was isolated as
the main phytotoxin
Papyracillic acidfrom a strain
(PA, 27, of 2,
Figure Ascochyta
Table 2),agropyrina var. nana,
a spiran complex which
toxin, waswas proposed
isolated as the
as bioherbicide to the control from Elytrigia repens. E. repens (quack grass)
main phytotoxin from a strain of Ascochyta agropyrina var. nana, which was proposed is a noxious
as bio-
perennial to
herbicide weed widespread
the control fromthrough
Elytrigiathe coldE.
repens. regions
repens of the northern
(quack grass) isand southern
a noxious hem-
perennial
ispheres.
weed widespread through the cold regions of the northern and southern hemispheres.

Figure 2. Fungal metabolites with potential for the biocontrol of plant pathogenic bacteria.
Pathogens 2024, 13, 1000 10 of 19

PA (27) showed toxicity towards the Gram-positive and Gram-negative bacteria such
as B. subtilis and Xanthomonas campestris, respectively, when tested at a range of concentra-
tions from 1.5 to 100 µg/disk. Compound 27 was also toxic against the fungus Candida
tropicalis at the concentration of 6.25 µg/disk [56]. Previously, papyracillic exhibited strong
antimicrobial, nematicidal and cytotoxic activity against Bacillus brevis, B. subtilis, Micro-
cossus luteus (Gram-positive) and Enterobacter dissolvens (Gram-negative) and against the
fungi Nematospora coryli, Mucor miehie, Penicillium notatum and Paecilomyces varioti [57].
PA (27) also exhibited nematicidal activity against Caenorhabditis elegans and Meloidogyne
incognita [58]. When tested at a range of concentrations of significant phytotoxic activity, a
different sensitivity was observed. Some key derivatives of PA were prepared and used
in a SAR study. PA (27) was converted to its methyl ester and methyl acetal by well-
known reactions with diazomethane and acid-catalyzed methanol, respectively, while its
acetylation afforded some acetyl derivatives, which resulted in an inseparable epimeric
mixture of the two monoacetyl derivatives in a ratio of ca. 1:1. The other two acetylated
compounds were a different monoacetyl and one of its diastereomers. In all the acetyl
derivatives, a cyclopentenone ring was preserved. By catalytic hydrogenation, PA gave
the expected dihydroderivative, with the saturation of the exocyclic methylene group.
All the PA and its derivatives were tested using a leaf disk–puncture assay at 1 mg/mL
concentration. The toxin was phytotoxic to both the host plant and several non-host plants,
while its derivatives showed significantly reduced activity compared to the toxin (27). A
structure–activity relationship (SAR) study revealed that the butenolide ring is a crucial
component for phytotoxicity and that the exocyclic methylene group at C-5 also plays a
role in inducing toxicity. In contrast, the tetrasubstituted tetrahydrofuran was found to be
non-essential. The reduced activity of the PA acetal further suggests that the hemiacetalic
hydroxy group at C-7 contributes to the toxin’s toxicity. As previously mentioned, the PA
was also effective against X. campestris, B. subtilis and C. tropicalis, while all the derivatives
in the same tests exhibited significantly lower toxicity than compound 27 [56].
Sphaeropsidin A (28, Figure 2, Table 2) is a tetracyclic pimarane diterpene produced
as the main phytotoxin by Diplodia cupressi (syn. of Sphaeropsis sapinea f. sp. cupressi), which
is the causal agent of the severe canker disease of Italian cypress (Cupressus sempervirens L.)
in the Mediterranean basin. Other phytopathogen species of Diplodia and some endophytic
fungal strain such as Tubercularia sp. and Smardaea sp. synthesize compound 28. The latter
toxin showed different and interesting biological activities, such as phytotoxic, antifungal
and antibiotic activity with potential applications in agriculture as biopesticides (natural
herbicides, fungicides and bacteriocides) and antiviral and anticancer activity, with poten-
tial in medicine to combat malaria, yellow fever and dengue. All the aspects of compound
28 including biosynthesis, isolation, characterization, biological activities, natural analogs,
hemisynthetic derivatives and the results of some SAR studies have been recently and
extensively reviewed [59].
More recently, some lipophilic derivatives of compound 28 were synthesized by mod-
ifying the C15 and C16–alkene moiety. Several of these derivatives induced significant
endoplasmic reticulum (ER) swelling, associated with proteasomal solid inhibition and
cell death—a mechanism not observed with the natural product itself. Analysis from the
National Cancer Institute’s screening of sixty cell lines showed no correlations between the
most potent derivative and other compounds in the database, except at high concentra-
tions (LC50, Lethal Concentration 50%). This study developed a new set of sphaeropsidin
derivatives that could be explored as potential anticancer agents, mainly due to their con-
tinued efficacy against multidrug-resistant models [60]. The authors Alexander Kornienko.,
Veronique Mathieu, Willem A. L. van Otterlo, Antonio Evidente, Aude Ingels A.I. and
Sachin B. Wagh are the inventors of the patent application PCT/US23/35648 (date of ap-
plication 21 October 2023). As regards a potential and significant application of diterpene
28 in agriculture, the toxin, sphaeropsidins B and C, two of its natural analogs, 14 of their
derivatives, which were obtained by chemical modifications of the toxins were assayed for
their antibacterial activity towards Xanthomonas oryzae pv. oryzae, Pseudomonas fuscovaginae
Pathogens 2024, 13, 1000 11 of 19

and Burkholderia glumae, which are the causal agents of severe bacterial rice diseases. The
proposed antibacterial activity of diterpene 28 and its natural analogs and derivatives
is based on their structural similarity to oryzalexins A-D [61–63] and momilactones A
and B [64], which are phytoalexins produced by Oryza sativa L. in response to attacks by
Pyricularia oryzae. These compounds have potential applications in the control of plant
diseases. Toxin 28 demonstrated specific and potent activity against Xanthomonas oryzae pv.
oryzae, while no toxicity was observed against the other two pathogens. Structure–activity
relationship (SAR) studies conducted with the cited derivatives of compound 28 indicated
that the key structural features essential for antibacterial activity include the presence
of the C-7 carbonyl group and hemiketal lactone functionalities. Additionally, the C-13
vinyl group, the double bond in ring C, the tertiary C-9 hydroxy group and the pimarane
arrangement of the tricyclic carbon skeleton were also found to contribute significantly to
the antibacterial properties [65].
SMA93, its 5-O-methyl, rhodolamprometrin, radicinin, dehydroallogibberic acid and
3-methyl-6,8-dihydroxyisocoumarin (29–34, Figure 2, Table 2) were isolated from Fusarium
proliferatum ZS07, a fungus obtained from long-horned grasshoppers (Tettigonia chinensis).
Compounds 30 and 32 inhibited the radicle growth of A. retroflexus L. seeds at a concentra-
tion of 100 µg/mL, with the inhibition rates of 83.0 and 65.2%, respectively. Compounds
29–31 exhibited antibacterial activity against B. subtilis (MIC values of 3.13–12.50 µg/mL)
but had no effect towards E. coli and Salmonella typhimurium [66].
Sphearopsidin A (28) was also produced, together with (R)-formosusin A, (R)-variotin,
candidusin and asperlin (35–38, Figure 2, Table 2) by Aspergillus candidus SFC20200425-M11,
which has the potential to reduce the development of fungal plant diseases such as tomato
late blight and wheat leaf rust. All the compounds were isolated, except compound 38,
showed antifungal activity against plant pathogenic fungi such as Alternaria brassicicola,
Botrytis cinerea, Colletotrichum coccodes, Fusarium oxysporum, Magnaporthe oryzae and Phytoph-
thora infestans (MIC ranging 1–250 µM/mL), but only asperlin (38) showed antibacterial
activity against Clavibacter michiganensis and E. amylovora with MIC values of 125 and
250 µg/mL, respectively [67].
Chloromonilicin (39, Figure 2, Table 2) was isolated for the first time, along with the
known phytotoxic polycyclic ethanones alternethanoxins A-E, from Alternaria sonchi, a
mycoherbicide proposed for controlling the noxious weed Sonchus arvensis. Chloromonilicin
(39) exhibited a broad spectrum of antimicrobial activity against bacteria, yeasts and plant
pathogenic fungi. When tested against B. subtilis, E. coli and P. fluorescens, compound
39 showed a minimum inhibitory concentration (MIC) of less than 0.5 µg per disk. It
was less effective against Paenibacillus polymyxa and C. tropicalis, with an MIC of around
1 µg per disk. Additionally, compound 39 inhibited the germination of conidia from
four widely distributed plant pathogenic fungi—Alternaria tenuissima, Bipolaris sorokiniana,
Colletotrichum gloeosporioides and Fusarium culmorum—with an MIC of less than 1 µg/mL.
Notably, compound 39 did not exhibit phytotoxicity against couch grass’s perennial sow
thistle or leaf segments. However, at a minimal concentration of 1 µg/mL, it inhibited the
movement of Paramecium caudatum within 1 h of treatment. The ciliates were killed at higher
concentrations (10 and 100 µg/mL) after 20 and 10 min of incubation, respectively [68].
Aspergyllone A (40, Figure 2, Table 2), a new 6-benzyl-γ-pyrone, was isolated to-
gether with the aurasperones A and D, asperpyrone A, fonsecinone A, carbonarone A and
pyrophen (41–46, Figure 2, Table 2) from the culture filtrates of an endolichenic fungus
Aspergillus niger Tiegh [69]. The fungus was collected from lichen thallus Parmotrema ravum
(Krog and Swinscow) Serus, in India. All the compounds were assayed for their antimi-
crobial activity and aspergyllone (40) showed strong selective antifungal activity against
Candida parapsilosis (IC50 of 52 mg/mL) and carbonarone A (45) exhibited activity against
Candida albicans and Candida krusei (IC50 (inhibitory concentration, 50%) 103 mg/mL and
31 mg/mL, respectively). Compound 45 also showed significant activity against a plant
pathogenic bacterium, Dickeya solani (IC50 88 mg/mL), which is the causal agent of blackleg
and slow wilt symptoms of potato plants in a number of European countries and Israel [70].
Pathogens 2024, 13, 1000 12 of 19

Aurasperone A (41) displayed antibacterial activity against Pseudomonas aeruginosa and S.

aureus (IC50 of 160 mg/mL and 135 mg/mL, respectively) and anti-candidal activity only
towards C. krusei (IC50 of 373 mg/mL). Fonsecinone A (44) inhibited only S. aureus and E.
coli (IC50 of 120 mg/mL and 47 mg/mL, respectively) and the plant pathogen, Pseudomonas
syringae pv. maculicola McCulloch with IC50 of 154 mg/mL. P. s. pv. maculicola caused leaf
spot and blight diseases of crucifer crops worldwide [71]. Asperpyrone A (43) exhibited
antibacterial activity against E. coli, with an IC50 value of 112 mg/mL. Pyrophen (46)
demonstrated promising antimicrobial properties, inhibiting 50% of the tested organisms,
including humans, fish and foodborne pathogens. It exhibited antifungal activity against
various Candida species, except C. krusei. Furthermore, significant antibacterial activity
was observed against Micrococcus luteus (IC50 63 mg/mL), Aeromonas hydrophila (IC50
78 mg/mL) and Listeria innocua (IC50 86 mg/mL). In contrast, Aurasperone D (42) showed
no antimicrobial activity [69]. Penicillic acid (47, Figure 2, Table 2) was isolated from Peni-
cillium sp. CRM 1540 obtained from Antarctic marine sediment as a potential bioinsecticide
against Xanthomonas citri subsp. citri, which is the causal agent of citrus canker. When tested
in vitro assays against X.campestris and X. citri subsp. citri, penicillic acid (47) showed MIC
for 90% growth inhibition of the bacterial cells of 49.39 and 25.0 µg/mL, respectively. In
greenhouse experiments, penicillic acid (25 µg/mL) suppressed citrus canker development
by 75.31% [72].
5-Hydroxymethyl-2-furancarboxylic acid (48, Figure 2, Table 2), was isolated from
Aspergillus niger xj together with ergosterol, β-sitosterol, 5-pentadecylresorcinol and succin-
imide [73]. All the compounds were tested against three plant pathogen bacteria, namely,
E. carotovora, whose effect on plant were cited above [74]; Agrobacterium tumefaciens, which
can infect 643 species of dicotyledonous plants and a few gymnosperm plants of 331 genera
and 93 families [75]; Ralstonia solanacearum, which is the causal agent of potato brown rot,
the bacterial wilt of tomato, tobacco, eggplant and some ornamental plants, as well as of
the Moko disease in bananas [76]. Compound 48 exhibited the most potent antibacterial
activity against the tested bacteria, with R. solanacearum being the most sensitive, showing
the lowest MIC of 15.56 µg/mL. These results suggest that the mechanism of action of com-
pound 48 against R. solanacearum may involve interference with bacterial protein synthesis
and intracellular metabolism. This hypothesis is supported by observations from scanning
electron microscopy, cell membrane permeability tests and SDS-PAGE analysis [73].

Table 2. Fungal metabolites with potential for the biocontrol of plant pathogenic bacteria.

Compounds Source Bacterium Target References

Ascochyta agropyrina var. Bacillus subtilis, Xanthomonas campestris, Bacillus
Papyracillic acid (27) [56]
nana brevis, Microcossus luteus Enterobacter dissolvens
Sphaeropsidin A (28) D. cupressi Xanthomonas oryzae pv. oryzae [65]
SMA93 (29) Fusarium proliferatum B. subtilis [66]
5-O-Methylated of SMA93 (30) “ “ “
Rhodolamprometrin (31) “ “ “
Radicinin (32) “ Not toxic “
Dehydrodroallogibberic acid (33), “ Not toxic “
3-Methyl-6,8-
“ Not toxic “
dihydroxyisocoumarin (34)
(R)-Formosusin A (35) Aspergillus candidus “ [67]
(R)-Variotin (36) “ “ “
Candidusin (37), “ “ “
Asperlin (38) “ Clavibacter michiganensis E. amylovora “
Pathogens 2024, 13, 1000 13 of 19

Table 2. Cont.

Compounds Source Bacterium Target References

B. subtilis, E. coli, P. fluorescens and Paenibacillus
Chloromonilicin (39) Alternaria sonchi [68]
polymyxa
Aspergillone (40) Aspergillus niger Not toxic [69]
Aurasperone A (41) “ Pseudomonas aeruginosa and S. aureus “
Aurasperone D (42) “ Not toxic “
Asperpyrone A (43), “ E. coli “
S. aureus, E. coli and Pseudomonas syringae pv.
Fonsecinone A (44) “ “
maculicola
Carbonarone A (45) “ Dickeya solani “
Micrococcus luteus, Aeromonas hydrophila and
Pyrophen (46) “ “
Listeria innocua
Xanthomonas citri subsp. citri, Xanthomonas
Penicillic acid (47) Penicillium sp. [72]
campestris
5-Hydroxymethyl-2- Erwinia carotovora, Agrobacterium tumefaciens,
Aspergillus niger xj [73]
furancarboxylic acid (48) Ralstonia solanacearum
“ means the same content.

4. Bacteriocides from Plants

The pond-raised channel catfish (Ictalurus punctatus) industry, has great economic
importance in United States, particularly in the southeastern region. Thus, environmentally
derived pre-harvest off-flavors, due to cyanobacterium Planktothrix perornata (Skuja) [77]
and the bacterial disease columnaris, and the enteric septicemia of catfish (ESC) caused
by Flavobacterium columnare and Edwardsiella ictaluri, respectively, resulted in significant
economic losses [78]. The classic control methods have low efficacy and selectivity [79].
Ungeremine (49, Figure 3, Table 3), an alkaloid isolated from a variety of Amaryllidaceae
plant species, including Ungernia minor, Crinum americanum, Crinum asiaticum, Zephyranthes
flava and Pancratium maritimum [80], showed toxicity against E. ictaluri (IC50 and the
MIC values were 58.0 and 3.0 mg/L, respectively). Ungeremine was also among the
most toxic compounds towards F. columnare, as well as 1-O-acetyllycorine and 1,2-O,O’-
diacetyllycorine (50 and 51, Figure 3, Table 3) [80], which are hemisynthetic derivatives of
lycorine (57, Figure 3, Table 3), which is the main Amaryllidaceae alkaloid [81]. A SAR study
was carried out using several derivatives of ungeremine and lycorine, such as ungeremine
hydrochloride, ungeremine isomer, zefbetaine (52–54, Figure 3), anhydrolycorine lactame,
anhydrolycorine and pseudolycorine (55, 56, 58, Figure 3), respectively, and testing their
toxicity against F. columnare. The results revealed that the C ring’s aromatization and
the B ring’s oxidation at C-7 to an azomethine group are critical structural features for
antibacterial activity. Additionally, the position of the oxygenation on the C ring and the
presence of the 1,3-dioxole ring attached to the A ring of the pyrrolo[de]phenanthridine
skeleton also play significant roles in enhancing activity. Based on 24 h, 50% inhibition
concentration (IC50) results, ungeremine hydrochloride (52) showed toxicity comparable to
compound 49, while alkaloid 55 demonstrated the lowest activity. The water solubility of
analog 52 may enhance its potential as an effective feed additive, making it more practical
than ungeemine [82].
The bioactivity of the metabolites of oregano (Origanum vulgare) essential oil, grown in
the arid Andes region are not extensively studied. Thus, a study performed by GC-MS (Gas
Chromatography–Mass Spectrometry) showed the presence in the essential oil of oregano,
collected in the Atacama Desert, of the well-known thymol (15.9%) as the main metabolite,
Z-sabinene hydrate (13.4%), γ-terpinene (10.6%), p-cymene (8.6%), linalyl acetate (7.2%),
sabinene (6.5%) and carvacrol methyl ether (5.6%). This essential oil showed antibacterial
 additive, making it more practical than ungeemine [82].
The bioactivity of the metabolites of oregano (Origanum vulgare) essential oil, grown
in the arid Andes region are not extensively studied. Thus, a study performed by GC-MS
(Gas Chromatography–Mass Spectrometry) showed the presence in the essential oil of
Pathogens 2024, 13, 1000 oregano, collected in the Atacama Desert, of the well-known thymol (15.9%) as the14main of 19
metabolite, Z-sabinene hydrate (13.4%), γ-terpinene (10.6%), p-cymene (8.6%), linalyl ac-
etate (7.2%), sabinene (6.5%) and carvacrol methyl ether (5.6%). This essential oil showed
antibacterial
activity towardsactivity towards
S. aureus S. aureus and
and Salmonella Salmonella
enterica and theenterica and the phytopathogenic
phytopathogenic bacteria Erwinia
bacteria Erwinia rhapontici and X. campestris. Furthermore, oregano oil exhibited
rhapontici and X. campestris. Furthermore, oregano oil exhibited antibacterial activityantibac-
against
terial activity against bacteria associated
bacteria associated with food poisoning [83]. with food poisoning [83].

Figure 3.
Figure 3. Plant
Plant metabolites
metabolites with potential for
with potential for the
the biocontrol
biocontrol of
of plant
plant pathogenic
pathogenic bacteria.
bacteria.

Methyl 2,4,6-trihydroxybenzoate, aloe-emodin, kaempferol, (-)-epiafzelechin, rhein,

kaempferol-3-O-glycoside, kaempferol-3-O-gentiobiside and aloe-emodin-8-O-β-D-glucoside
(59–66, Figure 3, Table 3) were isolated from the leaf extracts of Cassia alata L., which demon-
strated significant efficacy against plant diseases caused by fungi such as Magnaporthe
oryzae, Phytophthora infestans, Colletotrichum coccodes and Puccinia recondita in vivo. Among
the isolated metabolites, compounds 61–66 exhibited in vitro antifungal activity against
M. oryzae and Phytophthora species, with rhein (63) notably inhibiting the mycelial growth
of Phytophthora species and effectively suppressing tomato late blight. Furthermore, com-
Pathogens 2024, 13, 1000 15 of 19

pound 63 showed the potent in vitro inhibition of Acidovorax avenae subsp. cattlvae growth,
with an IC50 of 2.5 µg/mL [84].
The Tithonia diversifolia leaves were macerated in water and the corresponding aqueous
fraction and essential oil were shown to contain phenols, tannins, favonoids, alkaloids,
terpenoids, sugars, saponins, hydrocarbonated and oxygenated monoterpenes, terpenoids
and sesquiterpenes. α-Terpineol, eucalyptol, camphor and α-pinene (were the main com-
pounds (20.3%, 14.6%, 14.3% and 13.5%, respectively). The aqueous extract inhibited
Bipolaris oryzae and Fusarium moniliforme (IC50 50 mg/mL), while the essential oil exhib-
ited toxicity towards the phytopathogenic bacteria X. oryzae pv. oryzae and Pseudomonas
fuscovaginae (MIC 125 µg/mL), and against the two cited fungi [85].

Table 3. Plant metabolites with potential for the biocontrol of plant pathogenic bacteria.

Compounds Source Bacterium Target References

Edwardsiella ictaluri,
Ungeremine (49) Pancratium maritimum [80]
Flavobacterium columnare
1-O-Acetyllycorine (50) “ “ “
1,2-O,O’-Diacetyllycorine (51) “ “ “
Lycorine (55) Sternbergia lutea “ [81]
Methyl 2,4,6-trihydroxybenzoate (59) Cassia alata L. Not toxic [84]
Aloe-emodin (60) “ “ “
Kaempferol (61) M. oryzae and Phytophthora sp.
(-)-Epiafzelechin (62) “ “ “
Acidovorax avenae subsp.
Rhein (63) “ “
cattlvaePhytophthora sp.
Kaempferol-3-O-glycoside (64) “ M. oryzae and Phytophthora sp. “
Kaempferol-3-O-gentiobiside (65) “ “ “
Aloe-emodin-8-O-β-D-glucoside (66) “ “ “
“ means the same content.

5. Conclusions
Biotic (pathogens) and abiotic stresses (climate changes) are the leading causes of heavy
yield loss, severely damaging agricultural plants and, thus, food production. Similar effects
were also observed on forest heritage and, consequently, on wood industries and nurseries.
To address these challenges, there is an urgent need to reduce dependence on chemical
pesticides, which have been extensively used over the past five to six decades. Thus,
eco-friendly methods for biological control plant diseases based on natural compounds
are intensely investigated. This review explored the potential of metabolites derived from
bacteria, fungi and plants as valuable tools for the biological control of phytopathogenic
bacteria and, in some instances, fungi. It discussed the findings of structure–activity
relationship studies, along with the modes of action and efficacy of specific specialized
metabolites. In conclusion, metabolomics shows great promise in identifying and screening
novel bioactive metabolites, which could accelerate the discovery of effective candidates
for sustainable plant protection. By incorporating metabolomics into screening methods,
we can hasten the development of more effective and environmentally friendly agricultural
practices. However, key challenges remain for the practical application of these promising
metabolites as natural bacteriocides. These challenges include scaling up production,
ensuring their efficacy in formulations and developing protocols for their field application.
Pathogens 2024, 13, 1000 16 of 19

Author Contributions: Conceptualization, P.R., G.C. and A.E.; methodology, P.R. and A.E.; software,
P.R., G.C. and A.E.; writing—original draft preparation, P.R., G.C. and A.E.; supervision, A.E.; project
administration, A.E. All authors have read and agreed to the published version of the manuscript.
Funding: This research received no external funding.
Institutional Review Board Statement: Not applicable.
Informed Consent Statement: Informed consent was obtained from all the subjects involved in this
study.
Data Availability Statement: The data source was obtained from the SciFinder research motor.
Conflicts of Interest: The authors declare no conflicts of interest.

References
1. Strobel, G.A. Phytotoxins. Annu. Rev. Biochem. 1982, 51, 309–333. [CrossRef] [PubMed]
2. Ballio, A.; Graniti, A. Phytotoxins and their involvement in plant diseases. Experientia 1991, 47, 751–826.
3. Bender, C.L. Bacterial phytotoxins. Methods Microbiol. 1998, 27, 169–175.
4. Durbin, R. Toxins in Plant Disease; Elsevier: Amsterdam, The Netherland, 2012.
5. Duke, S.O.; Dayan, F.E. Modes of action of microbially-produced phytotoxins. Toxins 2011, 3, 1038–1064. [CrossRef]
6. Dudler, R. The role of bacterial phytotoxins in inhibiting the eukaryotic proteasome. Trends Microbiol. 2012, 22, 28–35. [CrossRef]
[PubMed]
7. Thakur, A.; Sharma, V.; Thakur, A. Phytotoxins—A mini review. J. Pharmacogn. Phytochem. 2018, 7, 2705–2708.
8. Chen, H.; Singh, H.; Bhardwaj, N.; Bhardwaj, S.K.; Khatri, M.; Kim, K.H.; Peng, W. An exploration on the toxicity mechanisms of
phytotoxins and their potential utilities. Crit. Rev. Environ. Sci. Technol. 2022, 52, 395–435. [CrossRef]
9. Tringali, C. Bioactive Compounds from Natural Sources: Isolation, Characterization and Biological Properties; CRC Press: Boca Raton, FL,
USA, 2000.
10. García-Pajón, C.M.; Collado, I.G. Secondary metabolites isolated from Colletotrichum species. Nat. Prod. Rep. 2003, 20, 426–431.
[CrossRef]
11. Cimmino, A.; Masi, M.; Evidente, M.; Superchi, S.; Evidente, A. Fungal phytotoxins with potential herbicidal activity: Chemical
and biological characterization. Nat. Prod. Rep. 2015, 32, 1629–1653. [CrossRef]
12. Evidente, A.; Cimmino, A.; Masi, M. Phytotoxins produced by pathogenic fungi of agrarian plants. Phytochem. Rev. 2019, 18,
843–870. [CrossRef]
13. Dayan, F.E.; Duke, S.O. Natural compounds as next-generation herbicides. Plant Physiol. 2014, 166, 1090–1105. [CrossRef]
[PubMed]
14. Evidente, A. Specialized metabolites produced by phytotopatogen fungi to control weeds and parasite plants. Microorganisms
2023, 11, 843. [CrossRef]
15. Shettally, R.; Prasad, R.; Walia, D.S. Effect of chemical pesticides on the environment. Indian J. Environ. 1997, 17, 275–280.
16. Srivastav, A.L. Chemical fertilizers and pesticides: Role in groundwater contamination. In Agrochemicals Detection, Treatment and
Remediation; Prasad, M.N.V., Ed.; Butterworth-Heinemann: Oxford, UK, 2020; pp. 143–159.
17. Oerke, E.C. Crop losses to pests. J. Agric. Sci. 2006, 144, 31–43. [CrossRef]
18. Seiber, J.N.; Coats, J.; Duke, S.O.; Gross, A.D. Biopesticides: State of the art and future opportunities. J. Agric. Food Chem. 2014, 62,
11613–11619. [CrossRef]
19. Khursheed, A.; Rather, M.A.; Jain, V.; Rasool, S.; Nazir, R.; Malik, N.A.; Majid, S.A. Plant based natural products as potential
ecofriendly and safer biopesticides: A comprehensive overview of their advantages over conventional pesticides, limitations and
regulatory aspects. Microb. Pathog. 2022, 173, 105854. [CrossRef] [PubMed]
20. Macías-Rubalcava, M.L.; Sánchez-Fernández, R.E. Secondary metabolites of endophytic Xylaria species with potential applications
in medicine and agriculture. World J. Microbiol. Biotechnol. 2017, 33, 1–22. [CrossRef] [PubMed]
21. Tumbarski, Y.; Lante, A.; Krastanov, A. Immobilization of bacteriocins from lactic acid bacteria and possibilities for application in
food biopreservation. Open Biotechnol. J. 2018, 12, 25–32. [CrossRef]
22. Smits, T.H.; Duffy, B.; Blom, J.; Ishimaru, C.A.; Stockwell, V.O. Pantocin A, a peptide-derived antibiotic involved in biological
control by plant-associated Pantoea species. Arch. Microbiol. 2019, 201, 713–722. [CrossRef]
23. Vicente, T.F.; Félix, C.; Félix, R.; Valentão, P.; Lemos, M.F. Seaweed as a natural source against phytopathogenic bacteria. Mar.
Drugs 2022, 21, 23. [CrossRef]
24. Akmukhanova, N.R.; Leong, Y.K.; Seiilbek, S.N.; Konysbay, A.; Zayadan, B.K.; Sadvakasova, A.K.; Sarsekeyeva, F.K.; Bauenova,
M.O.; Bolatkhan, K.; Alharby, H.F.; et al. Eco-friendly biopesticides derived from CO2 -Fixing cyanobacteria. Environ. Res. 2023,
239, 117419. [CrossRef] [PubMed]
25. Surico, G.; Comai, L.; Kosuge, T. Pathogenicity of strains of Pseudomonas syringae pv. savastanoi and their indoleacetic acid deficient
mutants on olive and oleander. Phytopathology 1984, 74, 490–493.
Pathogens 2024, 13, 1000 17 of 19

26. Surico, G.; Evidente, A.; Iacobellis, N.S.; Randazzo, G. On the presence and level of different cytokinins in culture filtrate of
Pseudomonas syringae pv. savastanoi. In Proceedings of the Plant Pathogenic Bacteria: Proceedings of the Sixth International
Conference on Plant Pathogenic Bacteria, College Park, MD, USA, 2–7 June 1987; pp. 566–570.
27. Sisto, A.; Cipriani, M.G.; Morea, M. Knot formation caused by Pseudomonas syringae subsp. savastanoi on olive plants is
hrp-dependent. Phytopathology 2004, 94, 484–489. [PubMed]
28. Lavermicocca, P.; Lonigro, S.L.; Evidente, A.; Andolfi, A. Bacteriocin production by Pseudomonas syringae pv. ciccaronei NCPPB2355.
Isolation and partial characterization of the antimicrobial compound. J. Appl. Microbiol. 1999, 86, 257–265.
29. Lavermicocca, P.; Lonigro, S.L.; Valerio, F.; Evidente, A.; Visconti, A. Reduction of olive knot disease by a bacteriocin from
Pseudomonas syringae pv. ciccaronei. Appl. Environ. Microbiol. 2002, 68, 1403–1407. [CrossRef]
30. Evidente, A. Bioactive lipodepsipeptides produced by bacteria and fungi. Int. J. Mol. Sci. 2022, 23, 12342. [CrossRef]
31. Bassarello, C.; Lazzaroni, S.; Bifulco, G.; Lo Cantore, P.; Iacobellis, N.S.; Riccio, R.; Gomez-Paloma, L.; Evidente, A. Tolaasins A−E,
five new lipodepsipeptides produced by Pseudomonas tolaasii. J. Nat. Prod. 2004, 67, 811–816. [CrossRef]
32. Wong, W.C.; Preece, T.F. Identification of Pseudomonas tolaasii: The white line in agar and mushroom tissue block rapid pitting
tests. J. Appl. Bacteriol. 1979, 47, 401–407. [CrossRef]
33. Lo Cantore, P.; Lazzaroni, S.; Coraiola, M.; Serra, M.D.; Cafarchia, C.; Evidente, A.; Iacobellis, N.S. Biological characterization
of white line-inducing principle (WLIP) produced by Pseudomonas reactans NCPPB1311. Mol. Plant Microbe Interact. 2006, 19,
1113–1120. [CrossRef]
34. Mieczkowski, A.; Speina, E.; Trzybiński, D.; Winiewska-Szajewska, M.; Wińska, P.; Borsuk, E.M.; Podsiadła-Białoskórska, M.;
Przygodzki, T.; Drabikowski, K.; Stanczyk, L.; et al. Diketopiperazine-based, flexible tadalafil analogues: Synthesis, crystal
structures and biological activity profile. Molecules 2021, 26, 794. [CrossRef]
35. Stierle, A.C.; Cardellina, J.H.; Strobel, G.A. Maculosin, a hostspecific phytotoxin for spotted knapweed from Alternaria alternata.
Proc. Natl. Acad. Sci. USA 1988, 85, 8008–8011. [CrossRef] [PubMed]
36. Puopolo, G.; Cimmino, A.; Palmieri, M.C.; Giovannini, O.; Evidente, A.; Pertot, I. Lysobacter capsici AZ78 produces cyclo (L-
ProL-Tyr), a 2, 5-diketopiperazine with toxic activity against sporangia of Phytophthora infestans and Plasmopara viticola. J. Appl.
Microbiol. 2014, 117, 1168–1180. [CrossRef]
37. Yamaguchi, T. Horticulture in Japan. 1994.
38. Young, J.M.; Fletcher, M.J. Pseudomonas syringae pv. panici (Elliott 1923) Young, Dye & Wilkie 1978 is a doubtful name. Australas.
Plant Pathol. 1994, 23, 66–68.
39. Liu, H.; Qiu, H.; Zhao, W.; Cui, Z.; Ibrahim, M.; Jin, G.; Li, B.; Zhu, B.; Xie, G.L. Genome sequence of the plant pathogen
Pseudomonas syringae pv. panici LMG 2367. J. Bacteriol. 2012, 194, 5693–5694. [CrossRef]
40. Mapuranga, N. A new race of Pseudomonas syringae pv. tabaci on tobacco in Zimbabwe. Plant Dis. 1998, 82, 1404.
41. Gutiérrez-Barranquero, J.A.; Cazorla, F.M.; de Vicente, A. Pseudomonas syringae pv. syringae associated with mango trees, a
particular pathogen within the “hodgepodge” of the Pseudomonas syringae complex. Front. Plant Sci. 2019, 10, 570.
42. Young, J.M. Pseudomonas syringae pv. japonica (Mukoo 1955) Dye et al. 1980 is a junior synonym of Ps. syringae pv. syringae van
Hall 1902. Lett. Appl. Microbiol. 1992, 15, 129–130.
43. Castaldi, S.; Cimmino, A.; Masi, M.; Evidente, A. Bacterial lipodepsipeptides and some of their derivatives and cyclic dipeptides
as potential agents for biocontrol of pathogenic bacteria and fungi of agrarian plants. J. Agric. Food Chem. 2022, 70, 4591–4598.
[CrossRef]
44. Böszörményi, E.; Érsek, T.; Fodor, A.; Fodor, A.M.; Földes, L.S.; Hevesi, M.; Hogan, J.S.; Katona, Z.; Klein, M.G.; Kormany, A.; et al.
Isolation and activity of Xenorhabdus antimicrobial compounds against the plant pathogens Erwinia amylovora and Phytophthora
nicotianae. J. Appl. Microbiol. 2009, 107, 746–759. [CrossRef]
45. Trippe, K.; McPhail, K.; Armstrong, D.; Azevedo, M.; Banowetz, G. Pseudomonas fluorescens SBW25 produces furanomycin, a
non-proteinogenic amino acid with selective antimicrobial properties. BMC Microbiol. 2013, 13, 111. [CrossRef]
46. McPhail, K.L.; Armstrong, D.J.; Azevedo, M.D.; Banowetz, G.M.; Mills, D. I: 4-Formylaminooxyvinylglycine, an herbicidal
germination-arrest factor from Pseudomonas rhizosphere bacteria. J. Nat. Prod. 2010, 73, 1853–1857. [CrossRef] [PubMed]
47. Kimbrel, J.A.; Givan, S.A.; Halgren, A.B.; Creason, A.L.; Mills, D.I.; Banowetz, G.M.; Armstrong, D.J.; Chang, J. H: An improved,
high-quality draft genome sequence of the Germination-Arrest Factor-producing Pseudomonas fluorescens WH6. BMC Genom.
2010, 11, 522. [CrossRef] [PubMed]
48. Mitchell, R.E.; Frey, E.J.; Benn, M.H. Rhizobitoxine and L-threo-hydroxythreonine production by the plant pathogen Pseudomonas
andropogonis. Phytochemistry 1986, 25, 2711–2715.
49. Sahm, U.; Knobloch, G.; Wagner, F. Isolation and characterization of the methionine antagonist L-2-amino-4-methoxy-trans-3-
butenoic acid from Pseudomonas aeruginosa grown on n-paraffin. J Antibiot. 1973, 26, 389–390. [CrossRef] [PubMed]
50. Braun, S.D.; Völksch, B.; Nüske, J.; Spiteller, D. 3-Methylarginine from Pseudomonas syringae pv. syringae 22d/93 suppresses the
bacterial blight caused by its close relative Pseudomonas syringae pv. glycinea. Chem. Bio Chem. 2008, 9, 1913–1920.
51. Katagiri, K.; Tori, K.; Kimura, Y.; Yoshida, T.; Nagasaki, T.; Minato, H. A new antibiotic. Furanomycin, an isoleucine antagonist. J.
Med. Chem. 1967, 10, 1149–1154. [CrossRef]
52. Xie, Y.; Peng, Q.; Ji, Y.; Xie, A.; Yang, L.; Mu, S.; Li, Z.; He, T.; Xiao, Y.; Zhao, J.; et al. Isolation and identification of antibacterial
bioactive compounds from Bacillus megaterium L2. Front. Microbiol. 2021, 12, 645484. [CrossRef]
Pathogens 2024, 13, 1000 18 of 19

53. Liu, C.; Bai, L.; Cao, P.; Li, S.; Huang, S.X.; Wa, J.; Li, L.; Zhang, J.; Zhao, J.; Song, J.; et al. Novel plant growth regulator
guvermectin from plant growthpromoting rhizobacteria boosts biomass and grain yield in rice. J. Agric. Food Chem. 2022, 70,
16229–16240. [CrossRef]
54. Zhang, M.; Li, L.; Li, C.; Ma, A.; Li, J.; Yang, C.; Chen, X.; Cao, P.; Li, S.; Zhang, Y.; et al. Natural product guvermectin inhibits
guanosine 5′ -monophosphate synthetase and confers broad-spectrum antibacterial activity. Int. J. Biol. Macromol. 2004, 267,
131510. [CrossRef]
55. Aghdam, N.M.N.; Baghaee-Ravari, S.; Shiri, A. Weeds associated bacterial endophyte producing pantocin against Pectobacterium
carotovorum subsp. carotovorum. J. Agric. Sci. Tech. 2024, 25, 1443–1454.
56. Evidente, A.; Berestetskiy, A.; Cimmino, A.; Tuzi, A.; Superchi, S.; Melck, D.; Andolfi, A. Papyracillic acid, a phytotoxic 1,6-
dioxaspiro [4,4] nonene produced by Ascochyta agropyrina var. nana, a potential mycoherbicide for Elytrigia repens biocontrol. J.
Agric. Food Chem. 2009, 57, 11168–11173.
57. Hansske, F.; Sterner, O.; Satadler, M.; Anke, H.; Dorge, L.; Shan, R. Papyracillic Acid, Method for Preparation and Its Use as
Synthon for Bioactive Substances. U.S. Patent 5907047, 25 May 1999.
58. Shan, R.; Heidren, A.; Stadler, M.; Sterner, O. Papyracillic acid, a new penicillic acid analogue from the ascomycete Lachnum
papyraceum. Tetrahedron 1996, 52, 10249–10254. [CrossRef]
59. Evidente, A. The incredible story of ophiobolin A and sphaeropsidin A: Two fungal terpenes from wilt-inducing phytotoxins to
promising anticancer compounds. Nat. Prod. Rep. 2024, 41, 434–468. [CrossRef] [PubMed]
60. Ingels, A.; Scott, R.; Hooper, A.R.; van der Westhuyzen, A.E.; Wagh, S.B.; de Meester, J.; Maddau, L.; Marko, D.; Aichinger, G.;
Berger, W.; et al. New hemisynthetic derivatives of sphaeropsidin phytotoxins triggering severe endoplasmic reticulum swelling
in cancer cells. Sci. Rep. 2024, 14, 14674. [CrossRef] [PubMed]
61. Akatsuka, T.; Kodama, O.; Kato, H.; Kono, Y.; Takeuchi, S. Short Communication 3-Hydroxy-7-oxo-sandaracopimaradiene
(oryzalexin A), a new phytoalexin Isolated from rice blast leaves. Agric. Biol. Chem. 1983, 47, 445–447.
62. Kono, Y.; Takeuchi, S.; Kodama, O.; Akatsuka, T. Absolute configuration of oryzalexin A and structures of its related phytoalexins
isolated from rice blast leaves infected with Pyricularia oryzae. Agric. Biol. Chem. 1984, 48, 253–255. [CrossRef]
63. Akatsuka, T.; Kodama, O.; Sekido, H.; Kono, Y.; Takeuchi, S. Novel phytoalexins (oryzalexins A, B and C) isolated from rice blast
leaves infected with Pyricularia oryzae. Part I: Isolation, characterization and biological activities of oryzalexins. Agric. Biol. Chem.
1985, 49, 1689–1694. [CrossRef]
64. Cartwright, D.; Langcake, P.; Pryce, R.J.; Leworthy, D.P.; Ride, J.P. Chemical activation of host defence mechanisms as a basis for
crop protection. Nature 1977, 267, 511–513. [CrossRef]
65. Evidente, A.; Venturi, V.; Masi, M.; Degrassi, G.; Cimmino, A.; Maddau, L.; Andolfi, A. In vitro antibacterial activity of
sphaeropsidins and chemical derivatives toward Xanthomonas oryzae pv. oryzae, the causal agent of rice bacterial blight. J. Nat.
Prod. 2011, 74, 2520–2525.
66. Li, S.; Shao, M.W.; Lu, Y.H.; Kong, L.C.; Jiang, D.H.; Zhang, Y.L. Phytotoxic and antibacterial metabolites from Fusarium
proliferatum ZS07 isolated from the gut of long-horned grasshoppers. J. Agric. Food Chem. 2014, 62, 8997–9001. [CrossRef]
67. Ngo, M.T.; Van Nguyen, M.; Han, J.W.; Kim, B.; Kim, Y.K.; Park, M.S.; Kim, H.; Choi, G.J. Biocontrol potential of Aspergillus
species producing antimicrobial metabolites. Front. Microbiol. 2021, 12, 804333. [CrossRef] [PubMed]
68. Cimmino, A.; Pescitelli, G.; Berestetskiy, A.; Dalinova, A.; Krivorotov, D.; Tuzi, A.; Evidente, A. Biological evaluation and
determination of the absolute configuration of chloromonilicin, a strong antimicrobial metabolite isolated from Alternaria sonchi. J.
Antibiot. 2016, 69, 9–14. [CrossRef] [PubMed]
69. Padhi, S.; Masi, M.; Panda, S.K.; Luyten, W.; Cimmino, A.; Tayung, K.; Evidente, A. Antimicrobial secondary metabolites of an
endolichenic Aspergillus niger isolated from lichen thallus of Parmotrema ravum. Nat. Prod. Res. 2020, 34, 2573–2580. [CrossRef]
[PubMed]
70. van Der Wolf, J.M.; Nijhuis, E.H.; Kowalewska, M.J.; Saddler, G.S.; Parkinson, N.; Elphinstone, J.G.; Pritchard, L.; Toth, I.K.;
Lojkowska, E.; Potrykus, M.; et al. Dickeya solani sp. nov., a pectinolytic plant-pathogenic bacterium isolated from potato (Solanum
tuberosum). Int. J. Syst. Evol. Microbiol. 2014, 64, 768–774. [CrossRef]
71. Takikawa, Y.; Takahashi, F. Bacterial leaf spot and blight of crucifer plants (Brassicaceae) caused by Pseudomonas syringae pv.
maculicola and P. cannabina pv. alisalensis. J. Gen. Plant. Pathol. 2014, 80, 466–474.
72. Vieira, G.; Khalil, Z.G.; Capon, R.J.; Sette, L.D.; Ferreira, H.; Sass, D.C. Isolation and agricultural potential of penicillic acid against
citrus canker. J. Appl. Microbiol. 2022, 132, 3081–3088. [CrossRef]
73. Wei, L.; Zhang, Q.; Xie, A.; Xiao, Y.; Guo, K.; Mu, S.; Xie, Y.; Li, Z.; He, T. Isolation of bioactive compounds, antibacterial activity,
and action mechanism of spore powder from Aspergillus niger xj. Front. Microbiol. 2022, 13, 934857. [CrossRef] [PubMed]
74. Avrova, A.O.; Hyman, L.J.; Toth, R.L.; Toth, I.K. Application of amplified fragment length polymorphism fingerprinting for
taxonomy and identification of the soft rot bacteria Erwinia carotovora and Erwinia chrysanthemi. Appl. Environ. Microbiol. 2002, 68,
1499–1508. [CrossRef]
75. Fuller, S.L.; Savory, E.A.; Weisberg, A.J.; Buser, J.Z.; Gordon, M.I.; Putnam, M.L.; Ghang, J.H. Isothermal amplification and
lateral-flow assay for detecting crown-gall-causing Agrobacterium spp. Phytopathology 2017, 107, 1062–1068. [CrossRef]
76. Mansfield, J.; Genin, S.; Magori, S.; Citovsky, V.; Sriariyanum, M.; Ronald, P.; Dow, M.; Verdier, V.; Beer, S.V.; Machados, M.A.;
et al. Top 10 plant pathogenic bacteria in molecular plant pathology. Mol. Plant Pathol. 2012, 13, 614–629. [CrossRef]
Pathogens 2024, 13, 1000 19 of 19

77. Schrader, K.K.; Dayan, F.E.; Allen, S.N.; de Regt, M.Q.; Tucker, C.S.; Paul, R.N., Jr. 9,10-Anthraquinone reduces the photosynthetic
efficiency of Oscillatoria perornata and modifies cellular inclusions. Int. J. Plant Sci. 2000, 161, 265–270. [CrossRef] [PubMed]
78. Klesius, P.H.; Evans, J.; Shoemaker, C. Advancements in fish vaccine development. Aquac Int. 2006, 4, 20–21.
79. Boyd, C.E.; Tucker, C.S. Pond Aquaculture Water Quality Management; Kluwer Academic Publishers: Boston, MA, USA, 1998;
p. 700.
80. Schrader, K.K.; Andolfi, A.; Cantrell, C.L.; Cimmino, A.; Duke, S.O.; Osbrink, W.; Wedge, E.W.; Evidente, A. A survey of
phytotoxic microbial and plant metabolites as potential natural products for pest management. Chem. Biodivers. 2010, 7, 2261–2280.
[CrossRef]
81. Kornienko, A.; Evidente, A. Chemistry, biology, and medicinal potential of narciclasine and its congeners. Chem. Rev. 2008, 108,
1982–2014. [CrossRef] [PubMed]
82. Schrader, K.K.; Avolio, F.; Andolfi, A.; Cimmino, A.ì.; Evidente, A. Ungeremine and its hemisynthesized analogs as bactericides
against Flavobacterium columnare. J. Agric. Food Chem. 2013, 61, 1179–1183. [CrossRef]
83. Simirgiotis, M.J.; Burton, D.; Parra, F.; López, J.; Muñoz, P.; Escobar, H.; Parra, C. Antioxidant and antibacterial capacities of
Origanum vulgare L. essential oil from the arid Andean Region of Chile and its chemical characterization by GC-MS. Metabolites
2020, 10, 414. [CrossRef]
84. Pham, D.Q.; Pham, H.T.; Han, J.W.; Nguyen, T.H.; Nguyen, H.T.; Nguyen, T.D.; Nguyen, T.T.T.; Cuong, T.H.; Pham, H.M.; Vu,
H.D.; et al. Extracts and metabolites derived from the leaves of Cassia alata L. exhibit in vitro and in vivo antimicrobial activities
against fungal and bacterial plant pathogens. Ind. Crops. Prod. 2021, 166, 113465. [CrossRef]
85. Dongmo, A.N.; Nguefack, J.; Dongmo, J.B.L.; Fouelefack, F.R.; Azah, R.U.; Nkengfack, E.A.; Stefani, E. Chemical characterization
of an aqueous extract and the essential oil of Tithonia diversifolia and their biocontrol activity against seed-borne pathogens of rice.
J. Plant Dis. Prot. 2021, 128, 703–713. [CrossRef]

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