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

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.

Keywords: bioanalytics; bioinformatics; drug discovery; genome mining; natural products.

Figure 1

Selected recent examples of RiPPs and their BGCs discovering by the genome mining approach. The structural genes within BGC-encoded precursor peptides are depicted in black.

Figure 2

Selected recent examples of NRPS-PKS hybrids (A,D), polycyclic tetramate macrolactam (B), and phosphonate family of NPs (C) and their biosynthetic gene cluster discovery using the genome mining approach.

Figure 3

Selected recent examples of NP discovery employing the metagenomic approach. (A) The hys and red gene clusters containing Trp dimerization enzyme sequence tag (depicted in green), which were expressed in S. albus and E. coli, respectively, afforded two new rare tryptophan dimers, hydroxysporine and reductasporine. (B) The malacidin BGC containing the Asp4 (the domain responsible for incorporating the first aspartic acid) gene sequence that was expressed in S. albus led to the production of malacidins A and B containing a rare 3-hydroxyl aspartic acid moiety (HyAsp, highlighted in purple). (C) The metagenome sequencing of the DNA sample of whole-tunicate D. molle E11-036 revealed the BGC of divamide A (the core peptide divamide A is shown in black).

Figure 4

Schematic of molecular networking (MN)-based dereplication.

Figure 5

Selected recent examples of NPs discovered by the MN-based approach and metabologenomics. (A) Polyketides. (B) Sphongonucleosides. (C) NRP and the hybrid NRPS-PKS. (D) Glycosylated NPs.