Microbial Bioactives
Microbial Bioactives | Online ISSN 2209-2161
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Volume 4 Number 1 2021
REVIEWS (Open Access)
Illuminating the Microbial Dark Matter: Biosynthetic Gene Cluster Discovery, Activation Strategies, and Bioactivity Assessment—A Systematic Review and Meta-Analysis
Md. Fakruddin 1*, SM Bakhtiar Ul Islam 1*
Microbial Bioactives 4 (1) 1-8 https://doi.org/10.25163/microbbioacts.4110711
Submitted: 07 January 2021 Revised: 01 March 2021 Accepted: 08 March 2021 Published: 10 March 2021
Abstract
Microbial secondary metabolites remain one of the most prolific sources of clinically relevant bioactive compounds, yet a substantial proportion of this chemical diversity remains inaccessible due to cryptic or transcriptionally silent biosynthetic gene clusters (BGCs). Advances in genome sequencing, metagenomics, and bioinformatics have revealed that microbial genomes harbor far more BGCs than the number of metabolites currently characterized, highlighting a significant gap between biosynthetic potential and realized chemistry. This systematic review and meta-analysis synthesize evidence on contemporary strategies for the detection, activation, and functional evaluation of microbial BGCs, with a particular focus on omics-driven discovery pipelines. Using PRISMA 2020 guidelines, studies were identified and screened to assess approaches including genome mining, metagenomic analyses, heterologous expression, chemical elicitation, and genetic manipulation for awakening silent clusters. Quantitative synthesis was performed where comparable bioactivity data were available, particularly for antitumor and antibacterial outcomes. The findings demonstrate that integrated workflows combining bioinformatics prediction, targeted activation strategies, and metabolomic profiling significantly enhance the discovery of novel secondary metabolites with measurable biological activity. Moreover, evidence across diverse ecological niches underscores the influence of environmental context on biosynthetic diversity and expression. Despite persistent challenges related to data integration, scalability, and annotation bias, the reviewed studies collectively indicate that systematic, multi-omics approaches are reshaping microbial natural product discovery. This work provides a consolidated framework for future efforts aimed at translating microbial genomic potential into next-generation therapeutics.
Keywords: Biosynthetic gene clusters; microbial secondary metabolites; genome mining; metagenomics; natural product discovery; systematic review; meta-analysis
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