UNIVERSITY OF SÃO PAULO

SCHOOL OF PHARMACEUTICAL SCIENCES OF RIBEIRÃO PRETO

Elicitation of natural products biosynthesis from endophytic

microorganisms´ interactions

Andrés Mauricio Caraballo Rodríguez

Ribeirão Preto

2016

UNIVERSITY OF SÃO PAULO

SCHOOL OF PHARMACEUTICAL SCIENCES OF RIBEIRÃO PRETO

Elicitation of natural products biosynthesis from endophytic microorganisms´

interactions

Tese de Doutorado apresentada ao Programa

de Pós-Graduação em Ciências Farmacêuticas

para obtenção do Título de Doutor em Ciências

Área de Concentração: Produtos Naturais e

Sintêticos

Dissertation submitted to the Pharmaceutical

Sciences Graduate Program in partial

fulfillment of the requirements for the degree

of Doctor in Philosophy.

Field of Study: Natural and synthetic products

PhD candidate: Andrés Mauricio Caraballo

Rodríguez

Advisor: Mônica Tallarico Pupo, PhD.

Corrected version of the doctoral dissertation submitted to the Pharmaceutical Sciences

Graduate Program 10/02/2017. The original version is available at the School of

Pharmaceutical Sciences of Ribeirão Preto/USP.

Ribeirão Preto

2016

i

ABSTRACT

CARABALLO-RODRÍGUEZ, A. M. Elicitation of natural products biosynthesis from

endophytic microorganisms´ interactions. 2016. 169 p. Doctoral Dissertation. School of

Pharmaceutical Sciences of Ribeirão Preto - University of São Paulo, Ribeirão Preto, 2016.

In order to continue with the study of natural products from previously isolated endophytes of

the Brazilian medicinal plant Lychnophora ericoides, the main goal of this work focused on

the metabolic exchange of endophytic microorganisms from this plant. As it has been

demonstrated during the last years, elicitation of different molecules is consequence of

microbial interactions, mainly due to the need to compete, survive and establish microbial

communities in shared environments. Recent mass spectrometry related approaches, such as

imaging and molecular networking, in combination with purification and structural elucidation

were applied to the current study of the microbial interactions of endophytes. During this study,

several chemical families were identified, such as polyene macrocycles, pyrroloindole

alkaloids, leupeptins, angucyclines, siderophores, amongst others. Amongst the polyene

macrocycles, the well-known antifungal amphotericin B was identified as a biosynthetic

product of the endophytic actinobacteria Streptomyces albospinus RLe7. When S. albospinus

RLe7 interacted with an endophytic fungus, Coniochaeta sp. FLe4, a red pigmentation was

observed. A new fungal compound was detected from microbial interactions. Isolation and

structure elucidation of this new compound enabled to demonstrate the elicitation of fungal

secondary metabolites by amphotericin B, an actinobacterial metabolite. It was also

demonstrated the elicitation of griseofulvin and its analogue dechlorogriseofulvin from another

endophytic fungus, FLe9, as a consequence of exposition to amphotericin B. In addition,

investigation of the chemical profile of another endophytic actinobacteria, S. mobaraensis

RLe3, led to reveal this strain as angucycline-derivatives producer. Besides that, coculturing

of this actinobacteria against Coniochaeta sp. FLe4 also demonstrated elicitation of

angucycline analogues. In conclusion, this study demonstrated elicitation of natural products

from microbial interactions as well as new compounds from endophytes from L. ericoides and

contributed to the identification of microbial metabolites.

Keywords: Endophytes; microbial interactions; natural products; molecular networking;

elicitation; amphotericin B.

ii

RESUMO

CARABALLO-RODRÍGUEZ, A. M. Eliciação da biossíntese de produtos naturais a partir

da interação de microorganismos endofíticos. 2016. 169 f. Tese de doutorado, Faculdade de

Ciências Farmacêuticas de Ribeirão Preto - Universidade de São Paulo, Ribeirão Preto, 2016.

Com o propósito de continuar com os estudos de produtos naturais de microorganismos

endofíticos da planta medicinal Brasileira Lychnophora ericoides, o principal objetivo desse

trabalho focou-se no estudo da troca metabólica de microorganismos endofíticos dessa planta.

Como tem sido demonstrado durante os últimos anos, a elicitação de diferentes compostos é

consequência das interações microbianas, principalmente devido à necessidade de competir,

sobreviver e estabelecer comunidades microbianas em diversos ambientes naturais.

Abordagens recentes de espectrometria de massas, tais como imageamento e molecular

networking, junto com purificação e elucidação estrutural foram aplicadas durante o estudo de

interações microbianas de endofíticos. Durante este estudo, várias classes químicas foram

identificadas, tais como polienos macrocíclicos, alcaloides pirroloindólicos, leupeptinas,

anguciclinas, sideróforos, entre outras. Da classe química de polienos macrocíclicos, foi

identificada a anfotericina B como produto da biossíntese da actinobactéria endofítica

Streptomyces albospinus RLe7. Durante a interação da S. albospinus RLe7 com o fungo

endofítico Coniochaeta sp. FLe4, uma pigmentação vermelha foi observada. Um novo

composto de origem fúngica foi detectado a partir de interações microbianas. O isolamento e

posterior elucidação estrutural do novo composto permitiu demonstrar a eliciação de

metabólitos secundários fúngicos pela anfotericina B, metabólito da actinobactéria S.

albospinus RLe7. Foi também demonstrada a eliciação de griseofulvina e desclorogriseofulvina

a partir de outro fungo endofítico, FLe9, como consequência da exposição à anfotericina B.

Adicionalmente, a investigação do perfil químico de outra actinobactéria endofítica, S.

mobaraensis RLe3, evidenciou essa linhagem como produtora de compostos da classe das

anguciclinas. Além disso, o cocultivo dessa actinobacteria com o fungo endofítico Coniochaeta

sp. FLe4 também eliciou análogos de anguciclinas. Em conclusão, neste estudo demonstrou-se

a elicitação de produtos naturais a partir das interações microbianas assim como de novos

compostos de endofíticos de L. ericoides e contribuiu-se com a identificação de metabólitos

microbianos.

Palavras-chave: Endofíticos. Interações microbianas. Produtos naturais. Molecular

Networking. Elicitação.

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1. INTRODUCTION

1.1. Relevance of endophytic microorganisms

The first report of an endophytic fungus was published more than a century ago (Freeman,

1904), describing the presence of a non-spore forming fungus in the seeds of Lolium

temulentum and suggesting a possible symbiotic relationship between the fungus and the host.

The term “endophyte” was later clarified in the biological context by considering that many

biological terms evolve over time (Wilson, 1995). The proposed definition considered not just

the location but also the infection strategy by the microorganism. Therefore, endophytes were

defined as fungi or bacteria that during all or part of their life cycle invade tissues of living

plants without causing symptoms of disease (Wilson, 1995). Interestingly, in that paper was

emphasized that, instead of being slaves of rules and definitions, the priority should be placed

on the biological context of the situation. As the question regarding to why infection by

endophytes does not trigger a defense response by the plant host (Wilson, 1995), a balanced

antagonism was proposed as a consequence of endophyte-host interaction (Schulz & Boyle,

2005; Schulz, Rommert, Dammann, Aust, & Strack, 1999). By investigating endophytes and

plant pathogens, it was found that a higher proportion of endophytes produced herbicidal

metabolites when compared to microorganisms isolated from other sources (Schulz et al.,

1999). Additionally, it was suggested that secondary metabolites produced by pathogens and

endophytes inhabiting the same host may be directed against each other in order to decrease

their competition (Schulz et al., 1999). This is a clear example of microbial metabolites as

mediators of biological responses in ecological contexts, such as plant-microorganisms

systems.

Endophytes became interesting as bioactive compounds sources since the first report of an

endophytic fungus, Taxomyces andreanae, producing the anticancer compound paclitaxel

(Stierle, Strobel, & Stierle, 1993). Paclitaxel (Figure 1) was further investigated and still

remains amongst one of the most effective chemotherapeutics currently used against cancer

(Cragg, Grothaus, & Newman, 2014; Newman & Cragg, 2016). Paclitaxel has been reported

from several endophytes (Somjaipeng, Medina, & Magan, 2016), including actinobacteria such

as Kitasatospora sp. (Caruso et al., 2000), as part of the efforts to find sustainable sources for

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this compound (Liu, Gong, & Zhu, 2016). After several years of research focused on obtaining

more amounts of this compound, the question about why endophytic microorganisms produced

the same compound as their hosts kept unanswered (Talbot, 2015). A relatively recent study

provided some answers and gave new insights into the fungi-host interaction, with paclitaxel as

one of the mediators of this relationship (Soliman et al., 2015; Soliman & Raizada, 2013).

Briefly, as paclitaxel acts as fungicide (Soliman, Trobacher, Tsao, Greenwood, & Raizada,

2013), yew tree formed a symbiotic relationship with taxol-producing endophytes to protect

itself against pathogen invasion (Soliman, Tsao, & Raizada, 2011). The endophyte protects

diving cells from paclitaxel phytotoxicity by storage in hydrophobic bodies. As a response to

pathogen elicitors, the hydrophobic bodies containing the antifungal are released by exocytosis

at the pathogen entry points. So, while plant-produced paclitaxel assists general immunity,

endophytic-produced paclitaxel might target immunity where plant cells cannot, finally

explaining why both organisms produce paclitaxel (Soliman et al., 2015).

Maytansine (Figure 1), another important anticancer and cytotoxic compound, was

discovered in 1970 from Putterlickia species and in other Celastraceae plants of the genus

Maytenus (Kupchan et al., 1977; Kupchan et al., 1972). Interestingly, it was demonstrated a

different localization of maytansine in plant tissues. While in Maytenus, it was localized in the

above-ground tissues; in Putterlickia plants this compound was accumulated in the roots

(Kupchan et al., 1977; Kupchan et al., 1972). Further investigation enabled to demonstrate that

maytansine was produced by an endophytic microbial community within the roots of

Putterlickia verrucosa and P. retrospinosa (Kusari, S. et al., 2014). Besides that, in Maytenus

serrata, maytansine is produced jointly by the endophytic bacterial community with the host

plant (Kusari, P. et al., 2016). Recent studies showed detection of new maytansinoids in P.

pyracantha (Eckelmann, Kusari, & Spiteller, 2016), opening up further questions addressed to

reveal the ecological relevance of maytansinoids in their plant-hosts.

A large number of publications about endophytic microorganisms focused on natural

products sources became available and several reviews highlight the importance of endophytic

fungi for the pursuit of natural products (Aly, Debbab, Kjer, & Proksch, 2010; Borges, W.,

Borges, K., Bonato, Said, & Pupo, 2009; Gunatilaka, 2006; Kharwar, Mishra, Gond, Stierle, &

Stierle, 2011; Schulz, Boyle, Draeger, Rommert, & Krohn, 2002; Suryanarayanan et al., 2009;

Verma, Kharwar, & Strobel, 2009; Wang & Dai, 2011) as well as endophytic actinobacteria

(Golinska et al., 2015; Qin, Xing, Jiang, Xu, & Li, 2011; Raja & Prabakarana, 2011) or

endophytes in general as sources for therapeutic uses in various fields (Gouda, Das, Sen, Shin,

& Patra, 2016). Endophytes can potentially be used for peptide based drugs (Abdalla &

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Matasyoh, 2014) or even other anticancer compounds, such as the pro-drug

deoxypodophyllotoxin (Kusari, S., Lamshoeft, & Spiteller, 2009), camptothecin (Venugopalan,

Potunuru, Dixit, & Srivastava, 2016) or solamargine (El-Hawary et al., 2016) (Figure 1),

amongst others. However, their use at industrial level will have to wait for further developments

(Kusari, S., Pandey, & Spiteller, 2013; Kusari, S. & Spiteller, 2011). Currently, as illustrated

with the paclitaxel investigations, the discussion about the real sources of several natural

products have turned into what those metabolites are doing in nature (Davies, 2013; Davies &

Ryan, 2012; Newman & Cragg, 2015; Talbot, 2015). An understanding of the chemical ecology

behind microbial interactions of endophytes will lead to reveal their inexhaustible biosynthetic

potential (Kusari, S., Hertweck, & Spitellert, 2012).

The role natural products may play in the endophyte-host plant interaction is a matter of

recent interest. Considering the wide range of biological activities already discovered for the

reported microbial metabolites, their role in nature may be suggested. Since microorganisms

use the chemical language to communicate and interact, one of the suggested roles may be the

interference in quorum sensing by attenuating virulence factors of pathogens, which means

quenching of pathogen quorum molecules (Kusari, P. et al., 2014). In nature, microbes and

plants are in a close association, and the study of population dinamics, gene expression as well

as metabolite production involving microbe-microbe and microbe-plant quorum sensing

phenomena will give further directions to completely understand these ecosystems (Kusari, P.,

Kusari, S., Spiteller, & Kayser, 2015). One example where a tripartite interaction mediated by

quorum sensing molecules illustrates the importance of chemical communication in ecological

systems. Pantoea agglomerans (olive plant epiphyte) and Erwinia toletana (endophyte), non-

pathogenic bacteria, are associated with olive knot disease. Both microorganisms release

homoserine lactones analogues (Figure 1), signals that modulate the virulence of Pseudomonas

savastanoi pv. Savastanoi, responsible pathogen for the disease (Hosni et al., 2011). The

interference in quorum sensing is generally mediated mainly by two enzymes, lactonase and

acylase, for quenching or degradating of homoserine lactone autoinducers (Hong, Koh, Sam,

Yin, & Chan, 2012). Interestingly, homoserine lactone acylase has been reported from

endophytic Streptomyces, which may be involved in suppressing the soft rot infection by

Pectobacterium carotovorum spp. carotovorum on potato (Chankhamhaengdecha, Hongvijit,

Srichaisupakit, Charnchai, & Panbangred, 2013). These findings show the complexity of

chemical communication in ecological systems. Biotechnological applications of natural

products for drug resistance can be fully exploited if factors such as autoinducer triggers,

production/release signals or even degradation systems are considered (Kusari, P. et al., 2015).

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Figure 1. Illustrative examples of natural products from endophytes.

The role of endophytes in plant growth has been also investigated (Gaiero et al., 2013;

Miliute et al., 2016). Plant promoting traits, such as production of indole-3-acetic acid (Figure

1), were observed in endophytes from apple phyllosphere (Miliute et al., 2016). Indole-3-acetic

acid is a phytohormone that stimulates cell division as well as formation of plant roots (Davies,

2010). The effect of bacterial endophytes was also investigated in Trigonella foenum-graecum

L. Four out of nine endophytic Bacillus sp., associated with that medicinal plant, showed a

significant impact on plant growth and besides that, contributed to the increase in diosgenin

biosynthesis, a steroid sapogenin (Jasim, Geethu, Mathew, & Radhakrishnan, 2015). In another

medicinal plant, Euphorbia pekinensis, the effective growth promotion as a consequence of

treatment with endophytic fungi was demonstrated. Interestingly, it was also proved that

treatment of plants with non-endophytic fungi, was not as effective as the treatment with

endophytes. These findings could be attributed to the production of phytohormones, such as

indole-3 acetic acid (Dai, Yu, & Li, 2008). The mechanisms behind the plant-growth promotion

by endophytic bacteria have been proposed as phytostimulation (through production of

phytohormones), biofertilization (by increasing access to nutrients) and biocontrol (by

protection against phytopathogens) (Bloemberg & Lugtenberg, 2001). A complete

understanding of the microbial community composition of the plant system is necessary to

predict the effectiveness of an endophyte to promote plant growth (Gaiero et al., 2013). Of

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course, more comprehensive tools, such as “omics” approaches, should be used to study

endophytes and reveal their role in the plant host (Kaul, Sharma, & Dhar, 2016). Even more

relevant for future research, after understanding the endophyte community dynamics, is how

these populations will be affected in an environment influenced by climate change (Gaiero et

al., 2013).

As microorganisms are still underexplored reservoirs of natural products, endophytes from

the Brazilian medicinal plant Lychnophora ericoides (falsa-arnica) were selected in this study

for investigation of their natural products profile. L. ericoides has been used in traditional

medicine for treatment of wounds, inflammation and pain and several studies focused on its

chemistry have been carried out (Borella, Lopes, Vichnewski, Cunha, & Herz, 1998; dos

Santos, Gobbo-Neto, Albarella, de Souza, & Lopes, 2005; Gobbo-Neto, L., dos Santos, et al.,

2008; Gobbo-Neto, L., Gates, & Lopes, 2008; Gobbo-Neto, L. et al., 2010; Gobbo-Neto, L. &

Lopes, 2008; Gobbo-Neto, L. et al., 2005; Sakamoto et al., 2003; Semir, Rezende, Monge, &

Lopes, 2011). As part of the efforts of our research at the Laboratory of Chemistry of

Microorganisms (LQMo) at the School of Pharmaceutical Sciences of Ribeirão Preto,

University of São Paulo, coordinated by Prof. Dr. Mônica T. Pupo, endophytic microorganisms

from L. ericoides were isolated and a first study including some of these actinobacteria strains

was recently published by our group (Conti et al., 2016). In light of the described studies and

the importance of endophytes for this research field, microbial interactions approaches were

used in this PhD thesis in order to investigate natural products from endophytes of L. ericoides.

1.2. Natural products from microbial interactions approaches

As it was mentioned in the previous section, microorganisms inhabiting plant tissues are

interacting with other microorganisms. One of the expected consequences of these interactions,

which has been the focus of several studies, is the production of secondary metabolites. Several

reviews have been published highlighting different strategies involving microbial interactions

in order to increase the metabolite diversity (Bertrand et al., 2014; Bode, Bethe, Hofs, & Zeeck,

2002; Marmann, Aly, Lin, Wang, & Proksch, 2014; Pettit, 2009; Rutledge & Challis, 2015;

Scherlach & Hertweck, 2009). These approaches are totally consistent with simulation of

ecological contexts since microorganisms are in continuous interactions with other

microorganisms and even macroorganisms (Suryanarayanan, T., 2013), as previously

6

described. However, it is well known that microbes establish different kinds of interactions such

as cooperative or competitive relationships (Abrudan et al., 2015; Ghoul & Mitri, 2016;

Stubbendieck & Straight, 2016), and most of in vitro microbial interactions have not been tested

in more natural settings (Hibbing, Fuqua, Parsek, & Peterson, 2010). Due to the lack of

knowledge of the complex regulatory factors that may influence the microbial biosynthetic

machinery, a random approach named OSMAC (One Strain – MAny Compounds) was

proposed in the last decade (Bode et al., 2002). Briefly, the concept establishes that by

modifying culture parameters such as culture vessels, culture media, fermentor size, pH,

dissolved oxygen, or even microbial interaction, the chemical diversity can be expanded. By

using the OSMAC approach, more than 100 compounds from 25 different structural classes

from only 6 microorganisms were isolated (Bode et al., 2002).

Microbial interactions approach, or coculture strategy, has been widely used to induce

microbial compounds of interest, and plenty of examples can be found in literature. For

instance, increased production of paclitaxel from Paraconiothyrium SSM001 when exposed to

endophytes from the same host, Taxus (yew) tree (Soliman & Raizada, 2013) was observed.

The induction of istamycins (Figure 2) in Streptomyces tenjimariensis up to twice-fold as a

consequence of the interaction with twelve out of 53 tested bacteria was reported (Slattery,

Rajbhandari, & Wesson, 2001). Microbial interactions between Pseudomonas aeruginosa and

Enterobacter sp., isolated from a marine environment, enabled the isolation of a blue

compound, identified as pyocyanin (Figure 2), as well as the correction of the structural

characterization of this compound by NMR due to previous misreported data in the literature

(Angell, Bench, Williams, & Watanabe, 2006). Cocultivation of marine fungi have resulted in

isolation of new alkaloids, marinamide and its methyl ester (Zhu & Lin, 2006), which chemical

structures were later revised and attributed to pyrrolyl 4-quinolone analogues (Figure 2) (Zhu,

Chen, Wu, & Pan, 2013), as well as a new xanthone, 8-hydroxy-3-methyl-9-oxo-9H-xanthene-

1-carboxylic acid methyl ether (Figure 2) (Li, C. et al., 2011). Microbial interaction between

Aspergillus fumigatus and Streptomyces peucetius led to the induction of the new metabolites,

fumiformamide and N,N’-((1Z, 3Z)-1,4-bis(4-methoxyphenyl)buta-1,3-diene-2,3-

diyl)diformamide (Figure 2), two known N-formyl derivatives and a xanthocillin analogue BU-

4704 (Zuck, Shipley, & Newman, 2011). The coculturing of the endophytic fungus Fusarium

tricinctum with the bacterium Bacillus subtilis led to the production of three new compounds,

macrocarpon C, 2-(carboxymethylamino)benzoic acid and (-)-citreoisocumarinol (Figure 2),

as well as the increased levels of known compounds of the chemical classes of pyrones, cyclic

depsipeptides and lipopeptides (Ola, Thomy, Lai, Broetz-Oesterhelt, & Prolcsch, 2013). Three

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new decalin-type tetramic acid analogues, N-demethyl-ophiosetin and pallidorosetins A/B,

were produced when Fusarium pallidoroseum was cocultured with Saccharopolyspora

erythraea (Figure 2) (Whitt, Shipley, Newman, & Zuck, 2014). Three novel macrolactams with

unprecedented skeletons, niizalactams A-C, were isolated when Streptomyces sp. NZ-6 was

cultured in presence of mycolic acid-containing bacterium Tsukamurella pulmonis TP-B0596

(Hoshino et al., 2015). Interestingly, the same strain T. pulmonis TP-B0596 induced the

production of eight new 5-alkyl-1,2,3,4-tetrahydroquinolines (Figure 2) (Sugiyama et al.,

2015) as well as a novel class of lipidic metabolites named streptoaminals (Figure 2) from

Streptomyces nigrescens HEK616 (Sugiyama et al., 2016).

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Figure 2. Illustrative examples of natural products from microbial interactions.

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A remarkable study supported the hypothesis that not only diffusible signals but also

intimate physical interactions contribute to microbial communication (Schroeckh et al., 2009).

In that study, it was demonstrated that the physical interaction of Aspergillus nidulans with

Streptomyces hygroscopicus led to stimulate the fungal biosynthesis of aromatic polyketides,

such as orsellinic acid, lecanoric acid, and cathepsin inhibitors F-9775A and F-9775B (Figure

2) (Schroeckh et al., 2009). Another outstanding study screened 657 coculture experiments

involving fungal strains by using a high-throughput UHPLC-TOF-MS-based metabolomic

approach. In this study, two types of inductions were observed, de novo biosynthesis and up-

regulation. Interestingly, most of the detected features (peaks) from monocultures (80%)

matched at least one reported compound from the DNP database ("Dictionary of Natural

Products,"), while the matches were zero when the induced features, corresponding to the

induced metabolites from coculture, where searched. This results suggest that the features

detected at the fungal interaction zones in cocultures may correspond to novel chemical

compounds, not included in natural products databases (Bertrand et al., 2013). Taking into

consideration that a single microbial compound may have an impact on the metabolism of

microorganisms inhabiting the same environment (Kusari, S. et al., 2013), exposing

microorganisms to simulated communities where chemical exchange occurs makes the

previous examples coherent with what may happen in natural contexts.

At this point it is necessary to highlight that the study of microbe-microbe interactions may

provide valuable information to decipher chemical communication in nature, a necessary step

before validate the findings in more complex microbial communities (Lareen, Burton, &

Schafer, 2016) as it may occur in natural systems. Besides that, multispecies interactions should

be studied since endophytes communities are diverse and complex, and consequently, may be

more involved in interactions with microbial competitors than with the plant host itself (van

Overbeek & Saikkonen, 2016). This is consistent, since microbes are part of essential consortia

(Newman & Cragg, 2015), no matter what the environment they inhabit.

Considering the genome size of 8 Mb in actinobacteria, up to 11 Mb in myxobacteria, and

more than 30 Mb in fungi, the enormous potential of microorganisms for production of small

molecules is big (Bode et al., 2002). This is consistent with recent genomic approaches, such

as metagenomics, showing global microbial biosynthetic diversity holds enormous potential for

natural products discovery (Charlop-Powers et al., 2015). The bottleneck lays in finding the

triggers for biosynthesis of the cryptic metabolites, although the regulation of antibiotic

production has been extensively investigated in microbial models such as S. coelicolor, but also

10

in nonmodel streptomycetes (Liu, Chater, Chandra, Niu, & Tan, 2013), giving directions for

regulation of secondary metabolites that can be extended perhaps in other actinobacteria.

Due to the relevance of small molecules as mediators of chemical responses during microbial

interactions, and the fact that the levels of those chemicals are very low for detection, the need

for more sensitive techniques is required. For that reason, mass spectrometry related tools were

applied to the current study of endophytes from L. ericoides.

1.3. Mass spectrometry related tools for microbial natural products

investigation

The necessity for more sensitive techniques that enable to detect small quantities of

microbial compounds can be illustrated with the yet-uncharacterized secondary metabolite

produced by human gut bacteria, colibactin, involved in colorectal cancer (Nougayrede et al.,

2006). After more than ten years of research, the chemical structure of this cryptic metabolite

remains unsolved (Bode, 2015). However, several approaches, including NMR, MS, genomics

and bioinformatics tools, have enabled to tentatively propose candidates for pre-colibactins

(Figure 3) (Li, Z. R. et al., 2015; Vizcaino & Crawford, 2015). A recent example given by the

identification of maytansinoids in plant tissues showed clearly the need for MS/MS data that

enable future studies to identify natural products without the necessity for isolating (Eckelmann

et al., 2016).

For that reason, techniques that enable to obtain enough chemical information from small

quantities of samples are relevant for the current research, including in the field of natural

products. Recent developments have occurred in the detection of microbial small molecules by

using mass spectrometry (MS) approaches. A first approach recently used, Matrix-Assisted

Laser Desorption/Ionization Time-Of-Flight Imaging Mass Spectrometry (MALDI-TOF IMS)

for detecting microbial small molecules has been developed ad widely used (Yang et al., 2012).

Basically, MALDI-TOF IMS offers the possibility to detect small molecules from agar pieces

containing cultured microorganisms, and also allows to visualize their distribution in two or

even three dimensions (Watrous et al., 2013). Several examples and even the discovery of novel

natural products and biotransformation processes have been published in the past few years

(Gonzalez et al., 2012; Moree et al., 2012). This technique has been also applied for monitoring

suppression of quorum sensing signals by endophytic bacteria from Cannabis sativa L. (Kusari,

11

P. et al., 2014). Besides that, it enabled to visualize the spatial distribution of metabolites in

situ, as illustrated by maytansine in the roots of Putterlickia verrucosa and P. retrospinosa,

enabling to prove the hypothesis of microbial endophytes as actual producers of the compound

(Kusari, S. et al., 2014).

Another MS-based approach is molecular networking. It consists in the comparison of

fragmentation patterns amongst different MS/MS spectra in order to find similarities amongst

them. This approach was initially applied for peptide identification (Guthals & Bandeira, 2012)

and it was then developed for microbial small molecules analysis, since every single molecule

can lead to a unique MS/MS spectra, such as a fingerprint and then similarities can be found in

structurally related compounds (Watrous et al., 2012; Yang et al., 2013). Molecular networking

has been important for detection and partial characterization of natural products, such as an

antifungal lipopeptide from the syringomycin family, thanamycin (Figure 3) (Watrous et al.,

2012).

As manual analysis of large MS/MS datasets results inefficient, a free access platform for

the automated analysis and cross correlation of natural products MS/MS data, named Global

Natural Products Social Molecular Networking (Wang, M. et al., 2016) (GNPS, gnps.ucsd.edu)

was recently developed. What can be done by using the GNPS workflow include storage and

organization of MS/MS data, generation and visualization of molecular networking,

dereplication of natural products, contribution to MS/MS natural products collection, sharing

and curate data. For dereplication purposes, which means finding known or already identified

natural products, based on comparison with MS/MS data the GNPS platform includes libraries

such as MassBank, ReSpect and NIST, as well as collection of natural products and

pharmacologically active compounds related to the National Institutes of Health (NIH) in the

United States (Wang, M. et al., 2016). Currently, the GNPS libraries contains more than

200.000 MS/MS spectra representing more than 22.000 compounds (Wang, M. et al., 2016).

However, the number of published natural products can be about 300.000 to 600.000 (Berdy,

2012), which means the total chemical space still remains to be covered. To demonstrate how

GNPS platform can support natural products discovery, a set of five analogues of a broad-

spectrum antibiotic, stenothricin, were identified and named stenothricin-GNPS 1-5. The most

abundant of these analogues was isolated successfully confirming its structural similarity

(Figure 3) (Wang, M. et al., 2016). Computational methods for detection and investigation of

small molecules using mass spectrometry data have been developed (Hufsky, Scheubert, &

Bocker, 2014). Recently, in silico approaches that enable to search experimental MS/MS

12

spectra have been proposed and successfully tested to compensate the lack of experimental data

(Allard et al., 2016).

Figure 3. Illustrative examples of natural products discovered by MS approaches and molecular networking.

Structural elucidation of new compounds based only by mass spectrometry or even elucidate

the fragmentation pathway for knowns compounds are challenging tasks even for experienced

mass spectrometrists (Chai, Wang, & Wang, 2016). However, as previously mentioned,

fragmentation patterns are fingerprints that help in finding structural relationship amongst

chemical families, as it has been widely reported by using molecular networking (Covington,

McLeanab, & Bachmann, 2016; Floros, Jensen, Dorrestein, & Koyama, 2016; Garg et al., 2015;

Mascuch et al., 2015; Nguyen et al., 2013; Okada, Wu, Mao, Bushin, & Seyedsayamdost, 2016;

Wang, M. et al., 2016; Watrous et al., 2012). Due to the extensive application of MS/MS, it is

still necessary to investigate the mechanisms for specific fragmentation reactions (Chai et al.,

2016) to fully support structural elucidation. At this point, it is important to keep in mind the

relevance of analyzing mass differences instead of defining the specific reactions involved in

each fragment formation, in order to use mass fragmentation as a useful tool for structural

elucidation (Demarque, Crotti, Vessecchi, Lopes, & Lopes, 2016).

120

5. CONCLUSIONS

Demonstrating the biological role for every molecule in nature is on the way, and the

investigation of natural products in microbial communities is more rational since

microorganisms are not alone in nature. Here we have demonstrated the impact of microbial

interactions, occurring amongst endophytes from Lychnophora ericoides, on their secondary

metabolites profile. The presence of antifungal (amphotericin-analogues), anticholinesterase

(physostigmine-analogues), protease inhibitors (leupeptin-analogues) and cytotoxic

(angucycline-analogues) compounds was revealed by using mass spectrometry related tools

during investigation of microbial interactions. In addition, the elicitation of microbial

metabolites was fully demonstrated by the action of amphotericin B, produced by S. albospinus

RLe7, on two endophytic fungi, Coniochaeta sp. FLe4 and the fungus FLe9. Interestingly,

elicitation was also demonstrated when Coniochaeta sp. FLe4 interacted with S. albospinus

RLe3 inducing the production of angucycline derivatives. Besides identifying natural products

during microbial interactions, how metabolic exchange may influence the establishment of

those communities was visualized. With this study, partial annotation for the ionizable

metabolome from single and interacting endophytic actinobacteria was provided. The

fragmentation spectra from all microbial natural products detected here are available (“living

data”) for future identification at the GNPS database repository. This is the first study of

endophytic actinobacteria from L. ericoides in simulated communities, and the correlation

between microbial exchange and colony growth may reflect a similar effect within their host in

nature. Finally, the field of natural products has been benefited due to several advances for the

support of structural elucidation and more advances will support identification of natural

products in the years to come. Further work may reveal the specific biological role of small

molecules from microorganisms in different environments. In conclusion, this study

demonstrated elicitation of natural products from microbial interactions as well as new

compounds from endophytes from L. ericoides, contributed through identification of microbial

metabolites to the collaborative efforts of the scientific community in the field of natural

products, and opened the possibilities for future studies involving endophytes from L. ericoides.

121

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