Microbial natural products are a tremendous source of new bioactive chemical entities for drug discovery. Next generation sequencing has revealed an unprecedented genomic potential for production of secondary metabolites by diverse micro-organisms found in the environment and in the microbiota. Genome mining has further led to the discovery of numerous uncharacterized ‘cryptic’ metabolic pathways in the classical producers of natural products such as Actinobacteria and fungi. These biosynthetic gene clusters may code for improved biologically active metabolites, but harnessing the full genetic potential has been hindered by the observation that many of the pathways are ‘silent’ under laboratory conditions. Here we provide an overview of the various biotechnological methodologies, which can be divided to pleiotropic, biosynthetic gene cluster specific, and targeted genome-wide approaches that have been developed for the awakening of microbial secondary metabolic pathways.

Nucleoside antibiotics are a large class of pharmaceutically relevant chemical entities, which exhibit a broad spectrum of biological activities. Most nucleosides belong to the canonical N-nucleoside family, where the heterocyclic unit is connected to the carbohydrate through a carbon-nitrogen bond. However, atypical C-nucleosides were isolated from Streptomyces bacteria over 50 years ago, but the molecular basis for formation of these metabolites has been unknown. Here, we have sequenced the genome of S. showdoensis ATCC 15227 and identified the gene cluster responsible for showdomycin production. Key to the detection was the presence of sdmA, encoding an enzyme of the pseudouridine monophosphate glycosidase family, which could catalyze formation of the C-glycosidic bond. Sequence analysis revealed an unusual combination of biosynthetic genes, while inactivation and subsequent complementation of sdmA confirmed the involvement of the locus in showdomycin formation. The study provides the first steps toward generation of novel C-nucleosides by pathway engineering.

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Background The erratic alterations in climate being experienced in agriculture, such as extended periods of drought or heavy rainfalls, are bringing increasing concerns about nitrogen (N) management. Even in highinput farming systems, unpredictable weather patterns can cause N deficiencies and result in nutrient losses that contribute to major pollution issues in groundwater, lakes, and even the oceans. Our present understanding of the beneficial interactions between N-deficientchallenged plants and plant-associated bacteria (PAB), mainly of the phyla Actinobacteria, Bacteroidetes, Firmicutes, and Proteobacteria, is largely based on

Superbugs’ resistivity against available natural products has become an alarming global threat, causing a rapid deterioration in public health and claiming tens of thousands of lives yearly. Although the rapid discovery of small molecules from plant and microbial origin with enhanced bioactivity has provided us with some hope, a rapid hike in the resistivity of superbugs has proven to be the biggest therapeutic hurdle of all times. Moreover, several distinct mechanisms endowed by these notorious superbugs make them immune to these antibiotics subsequently causing our antibiotic wardrobe to be obsolete. In this unfortunate situation, though the time frame for discovering novel “hit molecules” down the line remains largely unknown, our small hope and untiring efforts injected in hunting novel chemical scaffolds with unique molecular targets using high-throughput technologies may safeguard us against these life-threatening challenges to some extent. Amid this crisis, the current comprehensive review highlights the present status of knowledge, our search for bacteria Achilles’ heel, distinct molecular signaling that an opportunistic pathogen bestows to trespass the toxicity of antibiotics, and facile strategies and appealing therapeutic targets of novel drugs. Herein, we also discuss multidimensional strategies to combat antimicrobial resistance.

Microbial natural products have been a cornerstone of the pharmaceutical industry, but the supply of novel bioactive secondary metabolites has diminished due to extensive exploration of the most easily accessible sources, namely terrestrial Streptomyces species. The Persian Gulf is a unique habitat for marine sponges, which contain diverse communities of microorganisms including marine Actinobacteria. These exotic ecosystems may cradle rare actinomycetes with high potential to produce novel secondary metabolites. In this study, we harvested 12 different species of sponges from two locations in the Persian Gulf and isolated 45 symbiotic actinomycetes to assess their biodiversity and sponge-microbe relationships. The isolates were classified into Nocardiopsis (24 isolates), Streptomyces (17 isolates) and rare genera (4 isolates) by 16S rRNA sequencing. Antibiotic activity tests revealed that culture extracts from half of the isolates displayed growth inhibitory effects against seven pathogenic bacteria. Next, we identified five strains with the genetic potential to produce aromatic polyketides by genotyping ketosynthase genes responsible for synthesis of carbon scaffolds. The combined data led us to focus on Streptomonospora sp. PA3, since the genus has rarely been examined for its capacity to produce secondary metabolites. Analysis of culture extracts led to the discovery of a new bioactive aromatic polyketide denoted persiamycin A and 1-hydroxy-4-methoxy-2-naphthoic acid. The genome harbored seven gene clusters involved in secondary metabolism, including a tetracenomycin-type polyketide synthase pathway likely involved in persiamycin formation. The work demonstrates the use of multivariate data and underexplored ecological niches to guide the drug discovery process for antibiotics and anticancer agents.

Members of the entomophagous fungi are considered very crucial in the fungal domain relative to their natural phenomenon and economic perspectives; however, inadequate knowledge of their mechanisms of interaction keeps them lagging behind in parallel studies of fungi associated with agro-ecology, forest pathology and medical biology. Ophiocordyceps sinensis (syn. Cordyceps sinensis), an intricate fungus-caterpillar complex after it parasitizes the larva of the moth, is a highly prized medicinal fungus known widely for ages due to its peculiar biochemical assets. Recent technological innovations have significantly contributed a great deal to profiling the variable clinical importance of this fungus and other related fungi with similar medicinal potential. However, a detailed mechanism behind fungal pathogenicity and fungal-insect interactions seems rather ambiguous and is poorly justified, demanding special attention. The goal of the present review is to divulge an update on the published data and provides promising insights on different biological events that have remained underemphasized in previous reviews on fungal biology with relation to life-history trade-offs, host specialization and selection pressures. The infection of larvae by a fungus is not a unique event in Cordyceps; hence, other fungal species are also reviewed for effective comparison. Conceivably, the rationale and approaches behind the inheritance of pharmacological abilities acquired and stored within the insect framework at a time when they are completely hijacked and consumed by fungal parasites, and the molecular mechanisms involved therein, are clearly documented.