Harnessing microbial secondary metabolites for modern medicine: A review

Microbial secondary metabolites have been an essential source of drug discovery for more than eight decades, and are currently influencing modern medicine, with an estimated half of all approved pharmaceuticals being of microbial natural product origin. Bacteria, fungi and actinomycetes produce these low-molecular-weight compounds, which exhibit remarkable chemical diversity and high biological activity, thus yielding clinically important antibiotics, antifungals, immunosuppressants and anticancer agents. Despite this achievement, therapeutic innovation has been limited by high rediscovery and an abysmal lack of contact between microbial genetic potential and experimentally observed metabolites. Genomic examination of biosynthetic gene clusters (BGCs) coded in microbial genomes indicates that most are silent or cryptic in standard laboratory environments, and that most environmental microorganisms are recalcitrant to growth, in total representing a huge pool of undiscovered chemical diversity. Recent developments in the field of genome mining, metagenomics, metabolomics, heterologous expression, epigenetic modulation, synthetic biology and gene-editing technologies like CRISPR-Cas9 have changed the discovery of secondary metabolites with systematic predictions, activation, and optimisation of these hidden pathways. This review attempts to synthesize vital insights along with recent computational and experimental studies to challenge microbial secondary metabolite biosynthesis, contemporary discovery strategies, and therapeutic uses.