Computer-aided Design of a Cyclic Di-AMP Synthesizing Enzyme CdaA Inhibitor

Overview

Journal Microlife

Publisher Oxford University Press

Specialty Microbiology

Date 2023 May 24

PMID 37223749

Authors

Piotr Neumann

Patrick Kloskowski

Ralf Ficner

Affiliations

Soon will be listed here.

Abstract

Cyclic di-AMP (c-di-AMP) is an essential secondary messenger regulating cell wall homeostasis and myriads of physiological processes in several Gram-positive and mycobacteria, including human pathogens. Hence, c-di-AMP synthesizing enzymes (DACs) have become a promising antibacterial drug target. To overcome a scarcity of small molecule inhibitors of c-di-AMP synthesizing enzyme CdaA, a computer-aided design of a new compound that should block the enzyme has been performed. This has led to the identification of a molecule comprising two thiazole rings and showing inhibitory potential based on ITC measurements. Thiazole scaffold is a good pharmacophore nucleus known due to its various pharmaceutical applications. It is contained in more than 18 FDA-approved drugs as well as in dozens of experimental drugs. Hence, the designed inhibitor can serve as a potent lead compound for further development of inhibitor against CdaA.

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