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Pharmacological validation of dihydrofolate reductase as a drug target in Mycobacterium abscessus .
- Source :
-
Antimicrobial agents and chemotherapy [Antimicrob Agents Chemother] 2024 Jan 10; Vol. 68 (1), pp. e0071723. Date of Electronic Publication: 2023 Nov 29. - Publication Year :
- 2024
-
Abstract
- 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 .<br />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.
- Subjects :
- Humans
Tetrahydrofolate Dehydrogenase genetics
Tetrahydrofolate Dehydrogenase metabolism
Trimethoprim pharmacology
Enzyme Inhibitors pharmacology
Folic Acid
Mycobacterium abscessus genetics
Mycobacterium abscessus metabolism
Folic Acid Antagonists pharmacology
Mycobacterium tuberculosis metabolism
Mycobacterium Infections, Nontuberculous drug therapy
Subjects
Details
- Language :
- English
- ISSN :
- 1098-6596
- Volume :
- 68
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Antimicrobial agents and chemotherapy
- Publication Type :
- Academic Journal
- Accession number :
- 38018963
- Full Text :
- https://doi.org/10.1128/aac.00717-23