EditorialSpecialized Bioactive Microbial Metabolites:From Gene to Product

Flavia Marinelli,1 Olga Genilloud,2 Victor Fedorenko,3 and Eliora Z. Ron4

1Department of Biotechnology and Life Sciences, University of Insubria andThe Protein Factory,Interuniversity Centre Politecnico di Milano, ICRM CNR Milano and University of Insubria, Varese, Italy2Fundacion MEDINA, Health Sciences Technology Park, Granada, Spain3Department of Genetics and Biotechnology, Ivan Franko National University of Lviv, Ukraine4Department of Molecular Microbiology and Biotechnology, Tel Aviv University and MIGAL Galil Research Center, Israel

Correspondence should be addressed to Flavia Marinelli; flavia.marinelli@uninsubria.it

Received 29 June 2015; Accepted 29 June 2015

Copyright © 2015 Flavia Marinelli et al.This is an open access article distributed under the Creative CommonsAttribution License,which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Natural products continue to play an important role in thediscovery of new therapeutic candidates. Over the past 30years, natural products or their derivatives have accountedfor 60% of new anticancer agents and almost 75% of allnew antibacterial molecules. One hundred natural prod-ucts and natural product-derived substances were beingevaluated in clinical trials or were being registered at theend of 2013. Bioactive molecules have been isolated frommany terrestrial and marine organisms, including plants,marine invertebrates, and microorganisms, the latter beingthe source selected more often for pharmaceutical drug dis-covery programs. Microorganisms (traditionally filamentousactinobacteria and fungi, but more recently cyanobacteria,microalgae, and myxobacteria) are one of the most prolificsources among living organisms for the production of bioac-tive molecules. Exploitation of their specialized (commonlynamed secondary) metabolism has guaranteed for decadesthe discovery of novel antibiotics and other compoundswith unprecedented chemical characteristics and biologicalproperties not existing in screening libraries of syntheticcompounds.

Despite the lack of big pharma interest in addressingthe topic in the last decade, microbial products continueto represent today one of the most interesting sources forthe discovery of novel drugs and research in the fieldis currently benefiting from progress that has been madein other related fields (microbial ecology, metagenomics,metabolomics, or synthetic biology), fields which have pro-vided a deeper understanding of the microbiome and thus

the development of new tools to foster the discovery ofnovel compounds. A wealth of microbial gene clusters thatencode novel biosynthetic pathways (or interesting variantsof those already described) to bioactive microbial products isbeing unveiled with the ever increasing number of sequencedmicrobial genomes. Whereas the difficulty to discover anddevelop in a reasonable time and acceptable cost new prod-ucts from microbial sources has been widely recognized,recent advances in genemining and heterologous expression,knowledge on regulatory networks, new analytical deconvo-lution, and chemical characterization tools are opening newavenues in the field of microbial product discovery.

This special issue includes five papers (three reviewsand two research papers) addressing diverse aspects relatedto the understanding and eventually facing the currentbottlenecks in the process ofmicrobial product discovery anddevelopment.

One of the papers is a review tracing the status onantibacterial discovery and development from microbialsources. Nowadays we are all aware that bacterial resistanceto all currently used antibiotics has emerged for both Gram-positive and Gram-negative bacteria. This threatening situa-tion urgently calls for a concerted international effort amonggovernments, the pharmaceutical industry, biotechnologycompanies, and the academic world to react and supportthe development of new antibacterial agents. The authorsof this review, which include the editors of this specialissue, after an introduction of the medical needs and themechanisms of antibacterial resistance, investigate those

Hindawi Publishing CorporationBioMed Research InternationalVolume 2015, Article ID 276964, 2 pageshttp://dx.doi.org/10.1155/2015/276964

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screening ingredients (i.e., how to build microbial productlibraries, methods for cultivation and extraction, the needof chemical dereplication for an early elimination of alreadyknown molecules, and tools for strain selection) that arenowadays crucial for discovering novel antibacterials. Anoverview of the current fermentation technology used toproduce specialized metabolites and a detailed analysis of thechances for genetically improving the producing microbes inthe postgenomics era are following. For themajority of antibi-otics, including those recently marketed, the only feasiblesupply process continues to be fermentation, total synthesisbeing too complicated or too expensive. Thus, manipulatingand improving microbial strains and their growing condi-tions remain the main tools to reduce production volumesand costs and guarantee quality and reproducibility of thedrug bulks.

A second review by researchers from Brazil is focussingon microalgae diversity exploitation for discovering andproducing interesting specialized metabolites endowed withanti-inflammatory, antimicrobial, and antioxidant activities.Microalgae are microorganisms that have different morpho-logical, physiological, and genetic traits: they include prok-aryotic (cyanobacteria) and eukaryotic organisms. Amongthe thousands of species of microalgae believed to exist, onlya small number are stored in collections around the world,and it is estimated that only a few hundred are investigatedfor interesting compounds present in their biomass. Afteran analysis of the product potentialities of genera such asNostoc, Spirulina, Chlorella, and Dunaliella, advantages andlimits of their cultivation and extraction are investigated. Dueto their photoautotrophicmetabolism,microalgal cultivationprocesses need to be better understood: microalgae canbecome an environmentally friendly and economically viablesource of compounds of interest, once their production isoptimized in a controlled culture and properly constructedbioreactors.

The third review written by South Korean researchersdiscusses the recent trends in the research and produc-tion of violacein, which is a purple pigment produced byboth natural and genetically modified bacterial strains. Thebisindole violacein is formed by the condensation of twotryptophan molecules through the action of five proteins.The genes required for its production, vioABCDE, and theregulatory mechanisms employed have been studied within asmall number of violacein producing strains. As a compound,violacein is known to have diverse biological activities,including as an anticancer agent and as an antibiotic againstStaphylococcus aureus and other Gram-positive pathogens.Identifying the biological roles of this pigmented molecule isof particular interest, and understanding violacein’s functionand mechanism of action has relevance to those unmaskingany of its commercial or therapeutic benefits. As usuallyhappens with specialized metabolites, the production ofviolacein and its related derivatives is strictly regulated andits production is limited. To face this production bottleneck,various groups are seeking to improve the fermentativeyields of violacein through genetic engineering and syntheticbiology.

The two research papers completing the issue are brilliantexamples of what was anticipated within the reviews ascritical steps in the discovery and development of novelspecialized metabolites. Interestingly, both of them are onlantibiotics, which represent an attractive option of a newclass of molecules that might overcome arising resistance.Lantibiotics are ribosomally synthetized and posttranslation-ally modified peptides possessing potent antimicrobial activ-ity against aerobic and anaerobic Gram-positive pathogens,including those increasingly resistant to 𝛽-lactams and gly-copeptides. For some of them, a specific mode of actioninhibiting cell wall biosynthesis (not antagonized by van-comycin) has been demonstrated, explaining the renewedinterest for such chemical class of antibacterial peptides.

The paper published by the Italian group deals withan example of an efficient strategy for lantibiotic screeningapplied to 240 members of a newly described genus offilamentous actinomycetes, named Actinoallomurus, whichis considered a yet-poorly exploited promising source fornovel bioactive metabolites. By combining antimicrobialdifferential assay against Staphylococcus aureus and its L-form(also in the presence of a 𝛽-lactamase cocktail or Ac-Lys-D-alanyl-D-alanine tripeptide), with LC-UV-MS dereplicationcoupled with bioautography and database query, a novelproducer of the potent microbisporicin complex was rapidlyidentified. Beside the interest in characterizing this novelproducer of microbisporicin, this paper drives the attentionto the relevance of the process termed dereplication, that is,the process of distinguishing those microbial extracts thatcontain known bioactive metabolites from those that containnovel compounds of interest, saving resources and speedingup the discovery process of novel drugs.

Finally, the last paper by a research group from Chinahighlights the need to improve the fermentation conditionsto sustain sublancin 168 production by a strain of Bacillussubtilis. Fermentation is the favourite way to produce thisantimicrobial peptide, but the authors claim that the lowyield of this stable lantibiotic, that has a broad spectrumof antimicrobial activity, has constrained its commercialapplication. In this specific case, the authors first screencarbon and nitrogen sources to identify key medium ingre-dients and then develop an experiment design approach tooptimize chemical composition of the cultivation mediumand temperature of incubation.The volumetric antimicrobialpeptide productivity was double and the study envisagesfurther increments that might be achieved following thedeveloped model.

Flavia MarinelliOlga Genilloud

Victor FedorenkoEliora Z. Ron

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