Recent Advances in Discovery of Lead Structures from Microbial Natural Products: Genomics- and Metabolomics-Guided Acceleration

Linda Sukmarini

doi:10.3390/molecules26092542

Abstract

Natural products (NPs) are evolutionarily optimized as drug-like molecules and remain the most consistently successful source of drugs and drug leads. They offer major opportunities for finding novel lead structures that are active against a broad spectrum of assay targets, particularly those from secondary metabolites of microbial origin. Due to traditional discovery approaches’ limitations relying on untargeted screening methods, there is a growing trend to employ unconventional secondary metabolomics techniques. Aided by the more in-depth understanding of different biosynthetic pathways and the technological advancement in analytical instrumentation, the development of new methodologies provides an alternative that can accelerate discoveries of new lead-structures of natural origin. This present mini-review briefly discusses selected examples regarding advancements in bioinformatics and genomics (focusing on genome mining and metagenomics approaches), as well as bioanalytics (mass-spectrometry) towards the microbial NPs-based drug discovery and development. The selected recent discoveries from 2015 to 2020 are featured herein.

Highlights

Natural products (NPs) originating from plants, animals, marine organisms, and from microbial sources continue to inspire novel discoveries in chemistry [1], biology [2], and medicine [3]
Given the rising limitations imposed by uncultivable strains and silent gene clusters, the integrative approach of bottom-up targeted screening, employing advanced analytical methods and guided by bioinformatics analysis, provides a promising alternative for unlocking the microbial metabolomes on an unprecedented scale
This approach eventually leads to disclosing the potential of microbial NP discovery [13,14,15]

Summary

Introduction

Natural products (NPs) originating from plants, animals, marine organisms, and from microbial sources continue to inspire novel discoveries in chemistry [1], biology [2], and medicine [3]. The sharp decline in discoveries arose with limitations of the traditional top-down screening approaches Those approaches, including bioassayand chemical signature-guided isolations, have largely been exhausted and may no longer be capable of delivering novel lead compounds [10]. Given the rising limitations imposed by uncultivable strains and silent gene clusters, the integrative approach of bottom-up targeted screening, employing advanced analytical methods and guided by bioinformatics analysis, provides a promising alternative for unlocking the microbial metabolomes on an unprecedented scale. This approach eventually leads to disclosing the potential of microbial NP discovery [13,14,15]. A genomic strategy uncovers the large number of microbial clustered genes (biosynthetic gene clusters) that encode the proteins responsible for the biosynthesis of a new NP that is undetected under standard fermentation conditions, while a metabolomics method embraces the global measurement of small-molecule metabolites from a microbe

Bioinformatics- and Genomics-Driven Discovery

Genome Mining Approach

Technological Advancements in Bioanalytics

Conclusions