Pharmacological validation of dihydrofolate reductase as a drug target in Mycobacterium abscessus .

Autor:	Aragaw WW; Center for Discovery and Innovation, Hackensack Meridian Health , Nutley, New Jersey, USA., Negatu DA; Center for Discovery and Innovation, Hackensack Meridian Health , Nutley, New Jersey, USA., Bungard CJ; Merck & Co., Inc. , West Point, Pennsylvania, USA., Dartois VA; Center for Discovery and Innovation, Hackensack Meridian Health , Nutley, New Jersey, USA.; Department of Medical Sciences, Hackensack Meridian School of Medicine , Nutley, New Jersey, USA., Marrouni AE; Merck & Co., Inc. , West Point, Pennsylvania, USA., Nickbarg EB; Merck & Co., Inc. , Boston, Massachusetts, USA., Olsen DB; Merck & Co., Inc. , West Point, Pennsylvania, USA., Warrass R; MSD Animal Health Innovation GmbH, Zur Propstei , Schwabenheim, Germany., Dick T; Center for Discovery and Innovation, Hackensack Meridian Health , Nutley, New Jersey, USA.; Department of Medical Sciences, Hackensack Meridian School of Medicine , Nutley, New Jersey, USA.; Department of Microbiology and Immunology, Georgetown University , Washington, USA.
Jazyk:	angličtina
Zdroj:	Antimicrobial agents and chemotherapy [Antimicrob Agents Chemother] 2024 Jan 10; Vol. 68 (1), pp. e0071723. Date of Electronic Publication: 2023 Nov 29.
DOI:	10.1128/aac.00717-23
Abstrakt:	The Mycobacterium abscessus drug development pipeline is poorly populated, with particularly few validated target-lead couples to initiate de novo drug discovery. Trimethoprim, an inhibitor of dihydrofolate reductase (DHFR) used for the treatment of a range of bacterial infections, is not active against M. abscessus . Thus, evidence that M. abscessus DHFR is vulnerable to pharmacological intervention with a small molecule inhibitor is lacking. Here, we show that the pyrrolo-quinazoline PQD-1, previously identified as a DHFR inhibitor active against Mycobacterium tuberculosis , exerts whole cell activity against M. abscessus . Enzyme inhibition studies showed that PQD-1, in contrast to trimethoprim, is a potent inhibitor of M. abscessus DHFR and over-expression of DHFR causes resistance to PQD-1, providing biochemical and genetic evidence that DHFR is a vulnerable target and mediates PQD-1's growth inhibitory activity in M. abscessus . As observed in M. tuberculosis , PQD-1 resistant mutations mapped to the folate pathway enzyme thymidylate synthase (TYMS) ThyA. Like trimethoprim in other bacteria, PQD-1 synergizes with the dihydropteroate synthase (DHPS) inhibitor sulfamethoxazole (SMX), offering an opportunity to exploit the successful dual inhibition of the folate pathway and develop similarly potent combinations against M. abscessus . PQD-1 is active against subspecies of M. abscessus and a panel of clinical isolates, providing epidemiological validation of the target-lead couple. Leveraging a series of PQD-1 analogs, we have demonstrated a dynamic structure-activity relationship (SAR). Collectively, the results identify M. abscessus DHFR as an attractive target and PQD-1 as a chemical starting point for the discovery of novel drugs and drug combinations that target the folate pathway in M. abscessus . Competing Interests: C.J.B., A.E.M., E.B.N., D.B.O., and R.W. are employees of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA.
Databáze:	MEDLINE
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