MICROBIAL METABOLITES AND SECONDARY METABOLISM: BIOCHEMICAL PATHWAYS IN DRUG DISCOVERY

Abstract

Microbes have been an amazing source of bioactive molecules, especially thanks to their secondary metabolism that results in the synthesis of structurally diverse metabolites that are incredibly valuable as drugs. Contrary to primary metabolites that are required for cell sustenance and reproduction, secondary metabolites are biosynthesized under certain circumstances and play adaptive functions, such as in antimicrobial defense, competitive advantage, and signaling. Such compounds especially those derived from actinomycetes, fungi, and endophytic bacteria, have significantly contributed to the development of antibiotics, immunosuppressors, anticancer agents and other drug leads. The biochemistry of secondary metabolism is elaborate and controlled by highly regulated enzymatic networks such as non-ribosomal peptide synthetases (NRPS), polyketide synthases (PKS), and hybrid pathways (with unprecedented chemical diversity and novel pharmacophores). Given the contributions of microbial secondary metabolism to modern drug discovery, the study of microbial secondary metabolism is undergoing a revolution driven by omics technologies and the bioinformatics and genome mining tools that rapidly exploit the massive datasets generated by these technologies. These methods enable the discovery of “silent” biosynthetic gene clusters, a subset of which will produce novel metabolites of unknown biological function. Moreover, advances in metabolic engineering and synthetic biology now allow the heterologous expression of these clusters in well-developed microbial hosts, which has led to enhanced titers, as well as to the generation of unprecedented structural divergency. Biochemical analyses have also uncovered that the expression of otherwise silent metabolic pathways can be initiated in response to environmental signals, or by epigenetic modifiers or microbes., leading to exciting new areas for therapeutics. This research is concerned with the biochemistry of microbial secondary metabolic pathways and their contribution to the development of drug lead discovery today. It provides a critical analysis of the role played by secondary metabolites as molecular architecture for drug design and discusses to what extent this can be useful in the development of new therapeutics. Furthermore, the thesis investigates possible shortcomings of existing screening approaches and introduces recent developments in pathway prediction and metabolite dereplication. Combining microbiological understanding with biochemical technologies, this work emphasizes the unexplored capabilities of microbial metabolism to fuel the mounting worldwide need for new drugs amidst rising antibiotic resistance and emerging diseases.