Cryptic metabolites and method for activating silent biosynthetic gene clusters in diverse microorganisms

Abstract

Microorganisms are prolific producers of natural products and are a group of molecules that make up the majority of drugs approved by the FDA in the past 35 years. After decades of mining, the low-hanging fruit has been picked and so the discovery of drug-like molecules from microorganisms has come to a near-halt. The reason for this lack of productivity is that most biosynthetic pathways that give rise to natural products are not active under typical laboratory growth conditions. These so-called cryptic or silent pathways are a major source of new bioactive molecules and methods that reliablyactivate them could have a profound impact on drug discovery. Disclosed herein is a rapid genetics-free method for eliciting and detecting cryptic metabolites using an imaging mass spectrometry-basedapproach. An organism of choice is challenged with elicitors from a small molecule library. The molecules elicited are then imaged by mass spec, which allows for rapid identification of cryptic metabolites. The cryptic metabolites are then isolated and characterized. The use of disclosed methods activates the production of recessive glycopeptides from actinomycete bacteria. The resulted molecules, the keratinimicins and keratinicyclins, are metabolites with important structural features. At least two of these, namely keratinimicins B and C, are highly bioactive against several pathogenic strains. The approach will allow for the rapid activation and identification of cryptic metabolites from diverse microorganisms in the future.

Description

[0001] Cross References to Related Applications [0002] This application claims priority to US Provisional Application No. 62 / 539,263, filed July 31, 2017, the entire contents of which are hereby incorporated by reference. [0003] References to Sequence Listings Submitted Electronically [0004] The electronically filed Sequence Listing is also incorporated herein by reference in its entirety (file name: PRIN-57276_ST25.txt; date created: July 13, 2018; file size: 524 bytes). technical field [0005] This article relates to recessive metabolites in general, and more specifically, to a set of recessive metabolites, and to genetics-free approaches for activating silent biosynthetic gene clusters in diverse microorganisms. Background technique [0006] Modern medicine is unthinkable without natural products. Isolated mainly from microorganisms and plants, these molecules are also known as secondary metabolites and form the basis of >70% of antibiotics, >50% of antican...

AI Technical Summary

Problems solved by technology

Although these approaches have collectively begun to elucidate the cryptic secondary metabolome of bacteria, they all require challenging culture, molecular biology, and / or genetic procedures that significantly slow down the progress and throughput of natural product discovery

Definitive methods to access recessive metabolites in various microorganisms are yet to be developed

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