2168 molecular bacteria-fungi interactions 2013

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Secondarymetabolites: organic

compounds that arenot essential for thegrowth of an organismbut are often endowed

with potent biologicalactivities to warrantsurvival of the species

Contents

I N T R O D U C T I O N . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 7 6

BACTERIA-FUNGI INTERACTIONS IN THE ENVIRONMENT . . . . . . . . . . . . . . 376

Bipartite Bacteria-Fungi Interactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 376

Tripartite Bacteria-Fungi-Plant Interactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 379

Tripartite Bacteria-Fungi-Animal Interactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 382

BACTERIA-FUNGI INTERACTIONS: EFFECTS ON FOODPRODUCTION AND SAFETY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 384

BACTERIA-FUNGI INTERACTIONS: EFFECTS ON MEDICINE . . . . . . . . . . . . . 386

Bacteria and Fungi as Coacting Human Pathogens .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 386

Exploiting Bacteria-Fungi Interactions for Drug Discovery . . . . . . . . . . . . . . . . . . . . . . . 388

CONCLUSIONS AND PERSPECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 389

INTRODUCTION

The discovery of penicillin is one of the first documented observations of an interaction betwe

bacteria and fungi mediated by small molecules. Historically molecular intergeneric interactio

were regarded mainly as growth-inhibiting interactions; however, modern research revealed th

microbial cross talk forms an integral part of our environment and covers various aspects beyon

simple antibiosis. There are instances in which natural products alter phenotypes and developme

tal processes, such as sporulation or biofilm formation, and serve as virulence factors in symbio

and pathogenic associations involving additional partners. Specialized mutualistic relationshi

have evolved in which a host organism harbors a symbiont to make use of its chemical synth

sis capabilities to combat competitors or to maintain a certain lifestyle. The growing number

studies published in the past few years that report discoveries in this field points to an excitin

emerging area of research. Our increasing understanding of the complex networks in microb

ecology will not only help us understand fundamental biological processes but also lead to the di

covery of new virulence factors and drug candidates. This review highlights recent contributio

to the understanding of bacteria-fungi interactions mediated by secondary metabolites that occ

in the environment and affect medicine and biotechnology.

BACTERIA-FUNGI INTERACTIONS IN THE ENVIRONMENT

Bipartite Bacteria-Fungi Interactions

Microbes ubiquitously occur in the environment and colonize almost every ecological niche. B

cause of this high abundance, different species coinhabit certain habitats and as a consequen

interact with each other. Such encounters probably represent the driving force to produce se

ondary metabolites that regulate the coexistence and survival of different species.

Interactions via antibiosis. Production of antimicrobial compounds provides a growth adva

tage for an organism that enables its survival in a competitive environment (112). A huge numb

of antibiotic and antifungal natural products have been identified since the beginning of t

golden age of antibiotics, and many of these compounds have been applied in medicine (1

Besides the medicinal importance, these works provided valuable insights into the ecologic

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Imaging massspectrometry:analytical technthat combines tuniversal detectcapability of ma

spectrometry wmicroscopic imtechniques and allows the visuaof biomoleculesbiological matri

function of the compounds and demonstrated how intricate and finely tuned bacteria-fungi in-

teractions in nature are. This is reflected by the different strategies that bacteria and fungi have

evolved to combat secreted antimicrobial compounds. For example, Schoonbeek et al. (145) re-

ported that broad-spectrum antibiotics produced byPseudomonasspp. (2,4-diacetylphloroglucinol,

phenazine-1-carboxylic acid, and phenazine-1-carboxamide) induce the expression of several ABC

transporter genes in the plant pathogenic fungusBotrytis cinerea, thus ensuring the efflux of toxic

metabolites.Fusariumspp. produce the mycotoxin fusaric acid, which is able to repress the pro-

duction of 2,4-diacetylphloroglucinol inPseudomonas fluorescensCHA0 by reducing the expression

of the responsible biosynthetic genes (110). In return, the biocontrol strainP. fluorescensWCS365

profits from the mycotoxin, as it appears to be a chemoattractant for this species (42). These

works also denote that antibiotics not only are chemical warfare agents, but presumably have

numerous additional functions in the microbial interplay. For instance, at subinhibitory con-

centrations, antibiotics may stimulate or depress bacterial gene expression at the transcription

level and thus affect virulence and metabolic and adaptive functions (58). Thus, secreted sec-

ondary metabolites might have manifold functions that we are only beginning to understand,

and further studies are needed to uncover the precise roles of natural products in microbial

ecology.

Bacteria as inducers of mushroom diseases. Bacteria-fungi interactions adapt to changing

environmental conditions. Within one genus of bacteria, organisms can be found that exert ei-

ther beneficial or detrimental effects on a fungal host. Well-studied examples are the interactions

between various Pseudomonasspecies and the cultivated mushrooms Agaricus bisporusand Pleu-

rotus ostreatus (3). Whereas Pseudomonas putida stimulates the fructification of A. bisporus(109,

129), other pseudomonads cause mushroom diseases (94, 136). Brown blotch disease, initiated by

P. tolaasiiand otherPseudomonasspp., accounts for significant crop losses in mushroom farming.

Typical symptoms include a dark brown discoloration of the mushroom caps accompanied by

characteristic lesions on the basidiocarp (152). The causal agents are tensioactive lipopeptides

named tolaasins that are produced by the bacteria (30). Tolaasins are cyclic lipodepsipeptides

consisting of 18 amino acids with -hydroxy-octanoic acid at the N terminus (9). Tolaasin I,

which is considered the main virulence factor, exhibits antimicrobial activity and is highly resis-

tant to enzymatic degradation (128). The characteristic symptoms of the disease are due to the

ability of tolaasin to disrupt the fungal cell membrane by forming transmembrane pores (20, 33).

Other known bacterial mushroom pathogens includePseudomonas gingeri(ginger blotch disease),

P. costantinii,P. aeruginosa, andP. fluorescens(56, 106). A related bacterium,Pseudomonasreactans,

has been proposed as a biocontrol strain to reduce blotch diseases, even though it is classified as

a mushroom pathogen (151).P. reactans produces in culture an extracellular peptide called the

white line inducing principle (WLIP), which is able to precipitate tolaasins (98). Pretreatment of

A. bisporuswith the isolated peptide protects the mushroom from brown blotch symptoms caused

by infection withP. tolaasii(3). WLIP consists of nine amino acids and an N-terminal fatty acid,

representing a potent biosurfactant with antimicrobial properties (98). The molecular basis for

the biosynthesis of this peptide in P. putidawas recently established (133).

Graupner et al. (60) described the first insights into the pathogenicity factors ofJanthinobac-

terium agaricidamnosum, which causes soft rot disease of A. bisporus (97). By monitoring the

infection process with imaging mass spectrometry, the authors identified the lipopeptide jagaricin

as a potent virulence factor. Genome mining and molecular genetic studies unequivocally estab-

lished that jagaricin is biosynthesized by a nonribosomal peptide synthetase. Furthermore, potent

antifungal properties of jagaricin were described, which indicates that the discovery of virulence

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Defensins: cationicpeptides produced byeukaryotes thatfunction as hostdefense molecules

-Butyrolactones:signaling moleculesproduced mainly bystreptomycetes thatregulate antibioticproduction andmorphologicaldifferentiation

Nonribosomalpeptide synthetases(NRPS):multifunctionalenzymes that catalyzethe biosynthesis ofpeptides

Polyketide synthase(PKS):multifunctionalenzyme that catalyzesthe oligomerization ofactivated smallcarboxylic acids;analogous to fatty acidsynthesis

factors involved in mushroom diseases may also contribute to the development of antifung

therapeutics.

Similarly, the discovery of the first defensin from a fungus, plectasin, underlined the impo

tance of studying natural bacteria-fungi interactions. Plectasin was isolated from the saprophy

ascomycetePseudoplectania nigrellaand acts by directly binding the bacterial cell wall precurs

lipid II (65, 107, 143). Owing to this rare mode of action, thefungaldefensin represents a promisi

lead for the development of new antibacterial agents.

Bacteria-fungi interactions in lichens. Lichens are mutualistic associations between fungi a

photoautotrophic organisms, i.e., green algae and cyanobacteria (43). The symbiotic partners for

complex and exposed structures that enable growth in diverse and even extreme environments th

usually are not favorable for the individual species (61). Secondary metabolites are hypothesiz

to contribute to the ability of lichens to survive in such rather hostile environments. For e

ample, lichens can endure high-UV exposition by synthesizing pigments that act as UV filte

(19). Moreover, it was shown several decades ago that lichen extracts possess antibiotic propert

(25), suggesting potential defense strategies of lichens. In many cases the mycobiont produces t

secondary metabolites (1, 38). However, more recent studies indicate that the photoautotroph

bacterial partner may also contribute biosynthetic capabilities. Yang et al. (165) reported t

formation of chlorinated -butyrolactones called nostoclides by cultures of the cyanobacteriuNostocsp. that were isolated from the lichen Peltigera canina. These compounds display mode

ate cytotoxic properties and may function as signalling molecules. Another well-known class

cyanobacterial metabolites are the microcystins, which are produced by aNostocspecies recover

from the lichenPannaria pezizoides(116). These cyclic heptapeptides were isolated from multip

genera of cyanobacteria and are strong hepatotoxins (45, 157). The biosynthesis of microcysti

by a large multifunctional enzyme complex containing both nonribosomal peptide syntheta

(NRPS) and polyketide synthase (PKS) modules is well studied (44). Kaasalainen et al. (82) ha

shown that microcystins are also produced in situ in the lichen and suggest that these peptid

act as deterrents for animal grazers. Cox et al. (35) analyzed Nostocstrains, among others, th

were isolated from diverse lichens and found that the formation of a neurotoxic amino acid,

N-methylamino-L-alanine, seems to be a common principle in cyanobacteria. Cryptophycins ahighly potent tubulin-depolymerizing polyketides isolated from cultures of the lichen cyanoba

terial symbiontNostocsp. ATCC 53789 (101). Because of their strong cytostatic activities, sever

semisynthetic derivatives were evaluated as potential anticancer agents (150). The finding th

lichen-derived cyanobacteria produce a number of highly toxic metabolites suggests an importa

function of the bacterial partner for the ecological fitness of the mutualistic association.

Furthermore, the close intergeneric association between fungi and photosynthetic organism

may be influenced by additional microbial partners (61). In many cases, lichens harbor a stab

consortium of various nonphotoautotrophic microorganisms including parasitic fungi and ev

endosymbiotic organisms (61). These coinhabiting species contribute to the mutualism, for e

ample, via secretion of secondary metabolites. Gonzalez et al. (59) isolated actinomycetes fro

lichens collected in tropical and cold areas and evaluated their biosynthetic capabilities. By PCtargeting secondary-metabolite-encoding biosynthetic genes, the authors proved the high biosy

thetic potential of the lichen-associated bacteria. Furthermore, the prevalence of these genes w

correlated to antimicrobial activities of the culture extracts (59). He et al. (68) isolated the b

naphthopyrones lichenicolins A and B from a lichen-associated fungus and reported antibacter

activity of lichenicolin A against gram-positive bacteria, suggesting an ecological function of t

associated microorganisms.



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Siderophores:ion-chelating agproduced by baand fungi to seqiron from theenvironment

Tripartite Bacteria-Fungi-Plant Interactions

In many cases, the microbial interplay is even more complex and involves additional partners.

Both bacteria and fungi live in close association with higher organisms and may exert beneficial

as well as detrimental effects on the coinhabiting species.

Bacteria-fungi interactions in the mycorrhizosphere. Fungi and bacteria are essential com-

ponents of terrestrial ecosystems (17). The root system of several plant species interacts with fungi

to form a symbiotic alliance called mycorrhiza (17, 153). Through this mutualistic interaction,plants benefit from enhanced access to minerals, and fungi profit from the carbohydrates of root

exudates (17). Whereas such trophic interactions have been extensively studied and were the focus

of a number of comprehensive reviews (5, 17, 48), only a little is known about the mechanisms

controlling these associations.

Among soil microbes, the arbuscular mycorrhizal fungi (AM fungi) represent one of the most

important classes, as they not only significantly influence the growth of plants but also impact the

development of other microbes coinhabiting the terrestrial ecosystem (5, 17). AM fungi belong

to the phylum Glomeromycota, and the establishment of a symbiotic relationship with plants is

usually not host specific (103). To engage in this mutualism, both partners have to communicate,

for example, via the exchange of signal molecules (67, 123). Plants secrete phytohormones such

as strigolactones to stimulate fungal metabolism and hyphal branching (2, 12). Fungi respond viaso-called Myc factors that control plant gene expression (17). In many cases this bipartite mutu-

alism is extended to a third bacterial partner. Several studies indicated the presence of bacteria in

the mycorrhizosphere (40, 108). Bacteria colonize mycorrhized roots, fungal hyphae, spores, and

fruiting bodies and even occur in the fungal cytoplasm. Their effect on the plant-fungus micro-

habitat is dynamic and multifaceted, ranging from the production of plant hormones to alleviating

stress and controlling pathogens (5, 17). The cooperation may vary in accordance with the current

ecophysiological state. Specific bacterial populations may facilitate the mycorrhizal establishment

(mycorrhization helper bacteria), for example, by excretion of organic acids that serve as a carbon

source for fungi (49). To ensure a stable physical interaction with the fungi, bacteria produce

extracellular polymers that aid attachment to the fungal surface (14). Soil prokaryotes may also

stimulate the growth of the fungi by triggering the germination of fungal spores (24, 70, 71).Tylka et al. (158) proposed that volatile compounds secreted by streptomycetes positively impact

AM fungal germination. Later, bacteria-produced auxofurans were identified as positive effectors

on fungal development (130) (Figure 1). Other important functions of such soil bacteria are the

detoxification of the fungal habitat and the protection against plant pathogens. Removal of fun-

gal waste products or changing the level of siderophores may facilitate mycorrhizal growth (50).

Budi et al. (24) reported that a Paenibacillusstrain isolated fromGlomus mosseaespores inhibits a

number of different plant fungal pathogens, thus showing a broad spectrum of activity. Bharadwaj

et al. (13) also studied the effect of AM fungal sporeassociated bacteria on plant pathogens and

evaluated the formation of siderophores. They found that a high number of bacteria inhibit the

growth of the plant pathogen Rhizoctonia solani, although the active compounds have not been

identified in this study. In addition, it was shown that 16 of 57 antagonistic isolates (fluorescentpseudomonads) produce siderophores (13). Because such bacterial chelators have a higher affin-

ity to ferric iron than fungal siderophores, it was suggested that the production of these small

molecules might contribute to the antagonistic activity against fungal pathogens (13). Citernesi

et al. (31) studied the influence of the biocontrol compound iturin A2, secreted byBacillus subtilis

strain M51, on AM fungi (31). The saprophytic growth of the fungusG. mosseaewas inhibited by

iturin A2 and no retardation in growth or establishment of symbiosis was noticed in the presence



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O

OCH3

ON

O

HO O

O O

O

HN

O

OH

O

OH

O

O

OCH3

ON

O

HOO

O O

Bacteria

Fungus

An

t

imicro

bials

An

t

imicro

bials

Symbiotic microorganisms

Pathogenic microorganisms

Mycorrhizosphere Endophytes

Rhizoxin

WF-1360F

Auxofuran

1H-indole-3-

acetic acid

Figure 1

Tripartite bacteria-fungus-plant interactions (specifically a pathogenic interaction causing rice seedling

blight). Symbiotic interactions in the mycorrhizosphere and in plant tissues and chemical mediators areshown. Double-headed arrow indicates interaction; stop lines indicate inhibition; orange ovals highlight thposition further modified by the fungus to increase phytotoxicity.

of the tomato host plant (Lycopersicon esculentum), whereas infection with competing species w

hindered. On the other hand, the fungal partner also might influence coinhabiting species v

the secretion of chemical substances. Besides nutritional effects, the exudation of antibiotics is

important fungal contribution to the mutualism. Thus, the fungus ensures the specific growth

symbiosis-promoting bacteria and prevents infection with antagonistic prokaryotes (40).

An even more complex network of cross-species interaction is exemplified by the interplay

bacteria living in the cytosol of AM fungi and their plant symbionts. Biancotto et al. (16) describ

CandidatusGlomeribacter gigasporarum, an endobacterium of the AM fungus Gigaspora magarita. Various insights into the lifestyle and maintenance of this mutualistic relationship we

gained (15, 79, 100, 137, 138). Full genome sequencing of the obligate endobacterium allowed

first glance into the evolution of the symbiosis and its ecological impact. Bioinformatic analysis

the sequence data suggested that the endobacteria could have the potential to synthesize vitam

B12, antibiotic-, and toxin-resistant molecules, which may contribute to the ecological fitness

the fungal host (53).



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Indoleacetic acid:a phytohormone thataffects growth anddevelopment of plants

to ensure the beneficial outcome of the mutualism. Diffusible chemical signals that coordina

the individuals in these populations might mediate the interaction. Bandara et al. (7) underto

first attempts to study the interaction between endophytic fungi and bacteria in vitro showing t

colonization of fungal mycelia by bacteria and the influence of biofilm formation on antimicrob

effects and production of indoleacetic acidlike substances (7) (Figure 1). Up to now the potent

of endophytic interspecies cross talk had hardly been exploited for the discovery of novel natur

products (86). Most studies focusing on the isolation of secondary metabolites from endophyt

have been carried out utilizing only axenic cultures. However, it can be assumed that a cocultu

of different species usually coinhabiting a plant might lead to the formation of novel compoun

as has recently been described for cocultures of actinomycetes and ascomycetes (see below).

Tripartite Bacteria-Fungi-Animal Interactions

The lifestyle and the survival of animals in tripartite animal-bacteria-fungi interactions depe

on the bacteria-fungi interplay. A remarkable example of the impact of bacteria-fungi interactio

on insects is the symbiosis of the European beewolf digger wasp (Philanthus triangulum) wi

Streptomycesspp. (83). The female wasps carry the bacteria in their antennal glands and distribu

them to the brood cell within the ground. Larvae harbor symbiotic bacteria in their cocoons th

protect them against pathogenic microorganisms. It was shown that the streptomycete symbio

is capable of producing a mixture of antibiotics containing streptochlorin (Figure 2) and eig

derivatives of piericidin under environmental conditions (85). Inhibition tests pointed toward

Bacteria

Fungus

AnimalsMycangimycin

Streptochlorin

Violacein

Dentigerumycin

HN

NH

NH

OHO

O

O

N

Cl

NH

HO

O O O

HN N

N

O

O

HN

OH

O

NHO

O

N

NH

O

HN O

OH

OOH

OO

NH

Figure 2

Schematic showing different tripartite interactions among bacteria, fungi, and animals. Selected naturalproducts mediating these interplays are displayed. Double-headed arrows indicate symbiotic interaction;bolts indicate damaging effect (dashed bolts indicate decreased damage due to bacteria-fungi interaction);stop lines indicate inhibition.



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Sufu: a fermentedsoybean productproduced by solid statefermentation of tofufollowed by an agingstep in brine

containing salt andalcohol

Mucormycosis:fungal infection causedby Mucorales

previously for the phytotoxin rhizoxin (118). Because some subspecies ofR. microsporusare us

for the fermentation of soybeans (e.g., for sufu and tempe production), a potential risk for hum

health arises from the toxinogenic symbiosis. Rhizonin is produced byBurkholderia endofungoru

the endosymbiont of aR. microsporusstrain originally isolated from groundnuts in Mozambiq

(119). The cyclic peptide is highly toxic to mammals as it causes serious hepatic lesions (16

The cytotoxic polyketide rhizoxin fromBurkholderia rhizoxinicais produced during fermentati

of soybeans withRhizopussp. for sufu production (132). Because some of the produced derivativ

belong to the strongest antimitotic agents known to date (141), a severe health risk may ari

for the consumer. These results underline the urgent necessity to consider potential detrimen

effects resulting from bacteria-fungi interactions during food production to warrant food safe

(89).

BACTERIA-FUNGI INTERACTIONS: EFFECTS ON MEDICINE

Bacteria and Fungi as Coacting Human Pathogens

Even though humans are colonized by numerous microorganisms, little is known about the mole

ular interaction among these organisms. However, this research area deserves particular attenti

because often mixed-species infections generate a complex scenario. The significance of unde

standing microbial interactions within human hosts is highlighted even further by the fact th

the disease outcome of mixed bacteria-fungi infections can differ from single-species infectio

(124), so that alternative treatment methods have to be applied. Usually, opportunistic pathoge

are involved in such multispecies infections. As a consequence, immunocompromised individu

are more prone to becoming infected. The bacteria-fungi interactions during an infection c

be characterized as either neutral (the interaction has no impact on the disease outcome), syne

gistic (bacterial and fungal pathogens act together against the human host), or antagonistic (t

microorganisms inhibit each other).

Rhizopus oryzaeis responsible for about 6080% of all human mucormycosis cases (75). Takin

into consideration thatRhizopusfungi have been found in association with endosymbiotic, toxi

producing bacteria (89), it appears plausible thatR. oryzaetoo may harbor endosymbionts. Exam

inations of clinical isolates identified bacteria-associated fungi as well as bacteria-free fungi (7

117). Utilizing mouse and fly models, Ibrahim et al. (75) investigated the impact of the endosym

biotic bacteria on the infection outcome. No difference in virulence was observed between th

fungi harboring bacterial endosymbionts and those without bacteria, although the endobacter

produced rhizoxin displays cytotoxic activity itself. Apparently, the Rhizopussp.Burkholderias

interaction is an example of a neutral interaction during infection (Figure 4). Still, it remai

unclear whether the same behavior can be expected during human infections.

Several synergistic interactions between human pathogenic fungi and bacteria have been d

covered and described. One intensely studied interaction is the coinfection of the yeastCryptococ

neoformansand the bacteriumKlebsiella aerogenes(Figure 4). Thereby, melanin is an important v

ulence factor forC. neoformans(28). Surprisingly, the yeast is not capable of synthesizing melan

on its own, so thatC. neoformansdepends on exogenous substrate.K. aerogenessupplies dopamin

which can be utilized for melanization byC. neoformans(47). The pigmentation protects the m

croorganisms not only against environmental stress but also against the human immune defen

(28). Another example of enhanced fungal virulence due to interspecies interplay is mixed biofilm

of the yeastCandida albicansand the bacteriumStreptococcus gordonii, which occur together in t

oral cavity (Figure 4). It was shown thatS. gordoniipromotes hyphal growth and biofilm formati

ofC. albicans (6). Both filamentous growth and biofilm formation contribute to the virulence



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Fungus

Human

Bacteria

No

BFI

NeutralBFI

AntagonisticBFI

Synergistic

BFI

Rhiz

oxin

S2

Farneso

l

Pyocyanin

3-oxo-C12-HSL

Melanin

AI-2

Dopamine

O

N

OCH3

O OO

HO

OH CO

OH

NCH

3

N

OH

NH

O

O

OO

OH

HN

O

ON

HHO

HO

NH2

O

OBOHO

HO OH

HO

Figure 4

Different medically important bacteria-fungi interactions (BFI). Double-headed arrows indicate interaction;bolts indicate disease (dashed bolts indicate less virulence due to bacteria-fungi interaction; bold boltsindicate enhanced virulence due to bacteria-fungi interaction); stop lines indicate inhibition. Abbreviations:3-oxo-C12-HSL, 3-oxo-C12-homoserine lactone; AI-2, autoinducer-2.

Autoinducer-2small, diffusiblequorum-sensingmolecule forinterspeciescommunication

the yeast (124). Bamford et al. (6) demonstrated that this interaction occurs via both physical and

chemical signals. The physical interaction takes place via adherence, and the interspecies signal

molecule autoinducer-2 serves as chemical signal (6).

The yeastC. albicansis involved in antagonistic bacteria-fungi interactions, too. An intensely

studied opponent ofC. albicansisPseudomonas aeruginosa (Figure 4). Both opportunistic pathogens

have been frequently isolated from burn victims (62) and cystic fibrosis patients (74). P. aeruginosaproduces a range of secondary metabolites that inhibit or even kill C. albicans. One of these

natural products is the antifungal phenazine pyocyanin (124). Notably, the pyocyanin precursor

5-methyl-phenazine-1-carboxylic acid (5MPCA) is even more potent than its end product (54).

Morales et al. (105) revealed the mechanism by which the antifungal activity is conferred. The

redox-active 5MPCA generates reactive oxygen species (ROS) such as H2O2and O2. In addition,

5MPCA reacts with amine moieties within proteins, thus impairing important cellular structures



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Histoneacetyltransferaacetylate-conserlysine residues ohistone

antibacterial activities against methicillin-resistant S. aureus. The emericellamide biosynthetic

genes were discovered via a gene deletion approach in the model organism Aspergillus nidulans,

offering the possibility to engineer novel analogues (29). Four new diterpenoids, libertellenones

AD, were discovered by coculturing the marine fungusLibertellasp. with an unidentified marine

bacterium (113). This bacterium seemed to specifically induce the formation of these compounds

in this fungal species as no new metabolites could be detected in 49 other cocultures with the

same bacterium. Zuck et al. (167) described the production of formyl-xanthocillin analogues by

using a mixed culture ofAspergillus fumigatusandStreptomyces peucetius.

In a more systematic approach, Schroeckh et al. (146) employed microarray-based monitoring

to study the expression of cryptic biosynthetic gene clusters in the model fungus A. nidulans

after induction through the interaction with actinomycetes sharing the same habitat. Of 58 tested

species, one strain (Streptomyces rapamycinicus) was detected that triggers the formation of the

archetypal polyketide orsellinic acid along with the typical lichen metabolite lecanoric acid and

two complex polyphenols with anti-osteoporosis activity. Molecular genetic studies allowed for

the first time the identification of the long-sought-after genetic locus for the biosynthesis of

orsellinic acid, one of the simplest fungal polyketides. Further insights into the mechanism of

the intimate interaction of both organisms were gained by studying the regulation of fungal

gene expression. By a systematic deletion of 36 out of 40 acetyltransferase-encoding genes and

by chromatin immunoprecipitation experiments, it was revealed that the bacterium induces a

histone modification in the fungus via the main histone acetyltransferase complex Saga/Ada (111).

These results demonstrate the complexity of bacteria-fungi interactions and imply the yet-to-be-

discovered potential of studying microbial cross talk.

CONCLUSIONS AND PERSPECTIVES

Various examples of bacteria-fungi interactions highlighted in this review illustrate that mixed

consortia of microorganisms are widespread and can be found in a variety of places including soil,

plants, animals, and humans and in food production. The more we understand these interactions

among bacteria and fungi, the more we realize that such interplays affect not only environmental

processes (e.g.,growth of plantsor diseases of plants, animals, fungi), butalso our everyday life (e.g.,

food production, food spoilage, human disease control). However, the molecular basis of some

important interkingdom interactions remains elusive. Moreover, one can presume that a plethora

of bacteria-fungi interactions awaits discovery. From a translational point of view, knowledge of

bacteria-fungi interactions can be exploited for beneficial use in many ways. Microorganisms that

control growth of spoilage or pathogenic organisms can replace synthetic chemicals used in the

food industry or during animal husbandry, fulfilling consumer demand for additive-free food and

organic farming. Obviously, the application of living organisms must be carefully considered. In

some cases it might be more suitable to use specific enzymes or natural products isolated from

an organism instead of the whole microbe. Natural product discovery has always been essential

for drug development. Utilizing cocultures in natural product-screening processes can aid the

discovery of novel secondary metabolites that are not produced in the absence of particular stimuli.

Another important medical benefit that can be gained from understanding the molecular basics

of bacteria-fungi interactions involved in human diseases is the identification of new therapeutic

targets to combat pathogens.

However, humans will be able to take advantage of bacteria-fungi interactions only if

they fully appreciate the molecular interplay. We expect future research to contribute greatly

to our understanding of bacteria-fungi interactions and to provide new avenues for novel

applications.



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DISCLOSURE STATEMENT

The authors are not aware of any affiliations, memberships, funding, or financial holdings th

might be perceived as affecting the objectivity of this review.

ACKNOWLEDGMENTS

K.S. and K.G. contributed equally to this review. We thank the International Leibniz Resear

School for Microbial and Biomolecular Interactions (ILRS) and the Jena School for MicrobCommunication ( JSMC) of the German Excellence Initiative for supporting the authors origin

research in this area.

LITERATURE CITED

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The Wonderful World of Archaeal Viruses

David Prangishvili 5

Tip Growth in Filamentous Fungi: A Road Trip to the Apex

Meritxell Riquelme 5

A Paradigm for Endosymbiotic Life: Cell Differentiation ofRhizobiumBacteria Provoked by Host Plant Factors

Eva Kondorosi, Peter Mergaert, and Attila Kereszt

6

Neutrophils VersusStaphylococcus aureus: A Biological Tug of War

Andras N. Spaan, Bas G.J. Surewaard, Reindert Nijland,

and Jos A.G. van Strijp 6

Index

Cumulative Index of Contributing Authors, Volumes 6367 6

Errata

An online log of corrections to Annual Review of Microbiology articles may be found

http://micro.annualreviews.org/

2168 molecular bacteria-fungi interactions 2013

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