Development of a Chemical Scaffold for Inhibiting Nonribosomal Peptide Synthetases in Live Bacterial Cells

Overview

Journal Beilstein J Org Chem

Specialty Chemistry

Date 2024 Mar 5

PMID 38440174

Authors

Fumihiro Ishikawa

Sho Konno

Hideaki Kakeya

Genzoh Tanabe

Affiliations

Soon will be listed here.

Abstract

The adenylation (A) domain is essential for non-ribosomal peptide synthetases (NRPSs), which synthesize various peptide-based natural products, including virulence factors, such as siderophores and genotoxins. Hence, the inhibition of A-domains could attenuate the virulence of pathogens. 5'---(Aminoacyl or arylacyl)sulfamoyladenosine (AA-AMS) is a bisubstrate small-molecule inhibitor of the A-domains of NRPSs. However, the bacterial cell permeability of AA-AMS is typically a problem owing to its high hydrophilicity. In this study, we investigated the influence of a modification of 2'-OH in the AMS scaffold with different functional groups on binding to target enzymes and bacterial cell penetration. The inhibitor with a cyanomethyl group at 2'-OH showed desirable inhibitory activity against both recombinant and intracellular gramicidin S synthetase A (GrsA) in the gramicidin S-producer ATCC 9999, providing an alternative scaffold to develop novel A-domain inhibitors.

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