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Open accessJournal ArticleDOI: 10.1039/D0NP00029A

The need to innovate sample collection and library generation in microbial drug discovery: a focus on academia

04 Mar 2021-Natural Product Reports (The Royal Society of Chemistry)-Vol. 38, Iss: 2, pp 292-300
Abstract: The question of whether culturable microorganisms will continue to be a viable source of new drug leads is inherently married to the strategies used to collect samples from the environment, the methods used to cultivate microorganisms from these samples, and the processes used to create microbial libraries. An academic microbial natural products (NP) drug discovery program with the latest innovative chromatographic and spectroscopic technology, high-throughput capacity, and bioassays will remain at the mercy of the quality of its microorganism source library. This viewpoint will discuss limitations of sample collection and microbial strain library generation practices. Additionally, it will offer suggestions to innovate these areas, particularly through the targeted cultivation of several understudied bacterial phyla and the untargeted use of mass spectrometry and bioinformatics to generate diverse microbial libraries. Such innovations have potential to impact downstream therapeutic discovery, and make its front end more informed, efficient, and less reliant on serendipity. This viewpoint is not intended to be a comprehensive review of contributing literature and was written with a focus on bacteria. Strategies to discover NPs from microbial libraries, including a variety of genomics and “OSMAC” style approaches, are considered downstream of sample collection and library creation, and thus are out of the scope of this viewpoint.

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Topics: Sample collection (61%)
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7 results found


Journal ArticleDOI: 10.1126/SCIENCE.ABD6919
Fan Zhang1, Miao Zhao1, Doug R. Braun1, Spencer S. Ericksen1  +18 moreInstitutions (2)
20 Nov 2020-Science
Abstract: New antifungal drugs are urgently needed to address the emergence and transcontinental spread of fungal infectious diseases, such as pandrug-resistant Candida auris. Leveraging the microbiomes of marine animals and cutting-edge metabolomics and genomic tools, we identified encouraging lead antifungal molecules with in vivo efficacy. The most promising lead, turbinmicin, displays potent in vitro and mouse-model efficacy toward multiple-drug-resistant fungal pathogens, exhibits a wide safety index, and functions through a fungal-specific mode of action, targeting Sec14 of the vesicular trafficking pathway. The efficacy, safety, and mode of action distinct from other antifungal drugs make turbinmicin a highly promising antifungal drug lead to help address devastating global fungal pathogens such as C. auris.

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Topics: Antifungal drug (70%), Candida auris (51%)

33 Citations


Journal ArticleDOI: 10.1039/D1NP00051A
Abstract: Covering: 1877 to 2020A key challenge in natural products research is the selection of biodiversity to yield novel chemistry. Recently, marine microorganisms have become a preferred source. But how novel are marine microorganism natural products compared to those reported from terrestrial microbes? Cluster analysis of chemical fingerprints and molecular scaffold analysis of 55 817 compounds reported from marine and terrestrial microorganisms, and marine macro-organisms showed that 76.7% of the compounds isolated from marine microorganisms are closely related to compounds isolated from terrestrial microorganisms. Only 14.3% of marine microorganism natural products are unique when marine macro-organism natural products are also considered. Studies targeting marine specific and understudied microbial phyla result in a higher likelihood of finding marine specific compounds, whereas the depth and geographic location of microorganism collection have little influence. We recommend marine targeted strain isolation, incorporating early use of genomic sequencing to guide strain selection, innovation in culture media and cultivation techniques and the application of cheminformatics tools to focus on unique natural product diversity, rather than the dereplication of known compounds.

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1 Citations


Open accessJournal ArticleDOI: 10.3390/MD19070371
Phuong-Y. Mai1, Phuong-Y. Mai2, Géraldine Le Goff1, Erwan Poupon2  +5 moreInstitutions (2)
26 Jun 2021-Marine Drugs
Abstract: Solid-phase extraction embedded dialysis (SPEED technology) is an innovative procedure developed to physically separate in-situ, during the cultivation, the mycelium of filament forming microorganisms, such as actinomycetes and fungi, and the XAD-16 resin used to trap the secreted specialized metabolites. SPEED consists of an external nylon cloth and an internal dialysis tube containing the XAD resin. The dialysis barrier selects the molecular weight of the trapped compounds, and prevents the aggregation of biomass or macromolecules on the XAD beads. The external nylon promotes the formation of a microbial biofilm, making SPEED a biofilm supported cultivation process. SPEED technology was applied to the marine Streptomyces albidoflavus 19-S21, isolated from a core of a submerged Kopara sampled at 20 m from the border of a saltwater pond. The chemical space of this strain was investigated effectively using a dereplication strategy based on molecular networking and in-depth chemical analysis. The results highlight the impact of culture support on the molecular profile of Streptomyces albidoflavus 19-S21 secondary metabolites.

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Topics: Dialysis (biochemistry) (50%)

Open accessPosted ContentDOI: 10.1101/2021.08.26.457769
26 Aug 2021-bioRxiv
Abstract: Microbial drug discovery programs rely heavily on accessing bacterial diversity from the environment to acquire new specialized metabolite (SM) lead compounds for the therapeutic pipeline. Therefore, knowledge of how certain bacterial taxa are distributed in nature, in addition to the degree of variation of SM production within those taxa, is critical to informing these front-end discovery efforts and making the overall sample collection and bacterial library creation process more efficient. In the current study we employed MALDI-TOF mass spectrometry and the bioinformatics pipeline IDBac to analyze diversity within phylotype groupings and SM profiles of hundreds of bacterial isolates from two Eunapius fragilis freshwater sponges, collected 1.5 km apart. We demonstrated that within two sponge samples of the same species, the culturable bacterial populations contained significant overlap in approximate genus-level phylotypes but mostly non-overlapping populations of isolates when grouped lower than the level of genus. Further, correlations between bacterial phylotype and SM production varied at the species level and below, suggesting SM distribution within bacterial taxa must be analyzed on a case-by-case basis. Our results suggest that two E. fragilis freshwater sponges collected in similar environments can exhibit large culturable diversity on a species-level scale, thus researchers should scrutinize the isolates with analyses that take both phylogeny and SM production into account in order to optimize the chemical space entering into a downstream bacterial library.

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Topics: Phylotype (55%), Sample collection (52%)

Open accessPosted ContentDOI: 10.1101/2021.08.11.456034
12 Aug 2021-bioRxiv
Abstract: Genome-mining is an important tool for discovery of new natural products; however, the number of publicly available genomes for natural product-rich microbes such as Actinomycetes, relative to human pathogens with smaller genomes, is small. To obtain contiguous DNA assemblies and identify large (ca. 10 to greater than 100 Kb) biosynthetic gene clusters (BGCs) with high-GC (>70%) and -repeat content, it is necessary to use long-read sequencing methods when sequencing Actinomycete genomes. One of the hurdles to long-read sequencing is the higher cost. In the current study, we assessed Flongle, a recently launched platform by Oxford Nanopore Technologies, as a low-cost DNA sequencing option to obtain contiguous DNA assemblies and analyze BGCs. To make the workflow more cost-effective, we multiplexed up to four samples in a single Flongle sequencing experiment while expecting low-sequencing coverage per sample. We hypothesized that contiguous DNA assemblies might enable analysis of BGCs even at low sequencing depth. To assess the value of these assemblies, we collected high-resolution mass-spectrometry data and conducted a multi-omics analysis to connect BGCs to secondary metabolites. In total, we assembled genomes for 20 distinct strains across seven sequencing experiments. In each experiment, 50% of the bases were in reads longer than 10 Kb, which facilitated the assembly of reads into contigs with an average N50 value of 3.5 Mb. The programs antiSMASH and PRISM predicted 629 and 295 BGCs, respectively. We connected BGCs to metabolites for N,N-dimethyl cyclic-ditryptophan, a novel lassopeptide and three known Actinomycete-associated siderophores, namely mirubactin, heterobactin and salinichelin. ImportanceShort-read sequencing of GC-rich genomes such as Actinomycetes results in a fragmented genome assembly and truncated biosynthetic gene clusters (often 10 to >100 Kb long), which hinders our ability to understand the biosynthetic potential of a given strain and predict the molecules that can be produced. The current study demonstrates that contiguous DNA assemblies, suitable for analysis of BGCs, can be obtained through low-coverage, multiplexed sequencing on Flongle, which provides a new low-cost workflow ($30-40 per strain) for sequencing Actinomycete strain libraries.

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Topics: Deep sequencing (62%), Sequence assembly (60%), Whole genome sequencing (59%) ... read more

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94 results found


Journal ArticleDOI: 10.1038/NRD1657
Abstract: Natural products and their derivatives have historically been invaluable as a source of therapeutic agents. However, in the past decade, research into natural products in the pharmaceutical industry has declined, owing to issues such as the lack of compatibility of traditional natural-product extract libraries with high-throughput screening. However, as discussed in this review, recent technological advances that help to address these issues, coupled with unrealized expectations from current lead-generation strategies, have led to a renewed interest in natural products in drug discovery.

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Topics: Drug discovery (52%)

2,130 Citations


Open accessJournal ArticleDOI: 10.1038/NATURE14098
Losee Lucy Ling1, Tanja Schneider2, Aaron J. Peoples1, Amy Spoering1  +17 moreInstitutions (3)
22 Jan 2015-Nature
Abstract: Antibiotic resistance is spreading faster than the introduction of new compounds into clinical practice, causing a public health crisis. Most antibiotics were produced by screening soil microorganisms, but this limited resource of cultivable bacteria was overmined by the 1960s. Synthetic approaches to produce antibiotics have been unable to replace this platform. Uncultured bacteria make up approximately 99% of all species in external environments, and are an untapped source of new antibiotics. We developed several methods to grow uncultured organisms by cultivation in situ or by using specific growth factors. Here we report a new antibiotic that we term teixobactin, discovered in a screen of uncultured bacteria. Teixobactin inhibits cell wall synthesis by binding to a highly conserved motif of lipid II (precursor of peptidoglycan) and lipid III (precursor of cell wall teichoic acid). We did not obtain any mutants of Staphylococcus aureus or Mycobacterium tuberculosis resistant to teixobactin. The properties of this compound suggest a path towards developing antibiotics that are likely to avoid development of resistance.

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Topics: Teixobactin (71%), Antibiotic resistance (54%), Lipid II (53%) ... read more

1,688 Citations


Journal ArticleDOI: 10.1038/NBT.4229
Abstract: Taxonomy is an organizing principle of biology and is ideally based on evolutionary relationships among organisms. Development of a robust bacterial taxonomy has been hindered by an inability to obtain most bacteria in pure culture and, to a lesser extent, by the historical use of phenotypes to guide classification. Culture-independent sequencing technologies have matured sufficiently that a comprehensive genome-based taxonomy is now possible. We used a concatenated protein phylogeny as the basis for a bacterial taxonomy that conservatively removes polyphyletic groups and normalizes taxonomic ranks on the basis of relative evolutionary divergence. Under this approach, 58% of the 94,759 genomes comprising the Genome Taxonomy Database had changes to their existing taxonomy. This result includes the description of 99 phyla, including six major monophyletic units from the subdivision of the Proteobacteria, and amalgamation of the Candidate Phyla Radiation into a single phylum. Our taxonomy should enable improved classification of uncultured bacteria and provide a sound basis for ecological and evolutionary studies.

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Topics: Bacterial taxonomy (58%), Phylogenetics (53%), Taxonomy (biology) (52%) ... read more

1,322 Citations


Open accessJournal ArticleDOI: 10.3389/FMICB.2010.00134
Rustam Aminov1Institutions (1)
Abstract: This article gives a very brief overview of the antibiotic era, beginning from the discovery of first antibiotics until the present day situation, which is marred by the emergence of hard-to-treat multiple antibiotic-resistant infections. The ways of responding to the antibiotic resistance challenges such as the development of novel strategies in the search for new antimicrobials, designing more effective preventive measures and, importantly, better understanding the ecology of antibiotics and antibiotic resistance are discussed. The expansion of conceptual frameworks based on recent developments in the field of antimicrobials, antibiotic resistance, and chemotherapy is also discussed.

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Topics: Antibiotic resistance (50%)

873 Citations


Journal ArticleDOI: 10.1038/NCHEMBIO841
William Fenical1, Paul R. Jensen1Institutions (1)
Abstract: Natural products are both a fundamental source of new chemical diversity and an integral component of today's pharmaceutical compendium. Yet interest in natural-product drug discovery has waned, in part owing to diminishing returns from traditional resources such as soil bacteria. The oceans cover 70% of the Earth's surface and harbor most of the planet's biodiversity. Although marine plants and invertebrates have received considerable attention as a resource for natural-product discovery, the microbiological component of this diversity remains relatively unexplored. Recent studies have revealed that select groups of marine actinomycetes are a robust source of new natural products. Members of the genus Salinispora have proven to be a particularly rich source of new chemical structures, including the potent proteasome inhibitor salinosporamide A, and other distinct groups are yielding new classes of terpenoids, amino acid–derived metabolites and polyene macrolides. The continued development of improved cultivation methods and technologies for accessing deep-sea environments promises to provide access to this significant new source of chemical diversity.

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712 Citations


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