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Pharmacological validation of dihydrofolate reductase as a drug target in Mycobacterium abscessus.
Aragaw, Wassihun Wedajo; Negatu, Dereje A; Bungard, Christopher J; Dartois, Véronique A; Marrouni, Abdellatif El; Nickbarg, Elliott B; Olsen, David B; Warrass, Ralf; Dick, Thomas.
Afiliación
  • 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.
  • Marrouni AE; Department of Medical Sciences, Hackensack Meridian School of Medicine , Nutley, New Jersey, USA.
  • Nickbarg EB; Merck & Co., Inc. , West Point, Pennsylvania, USA.
  • Olsen DB; Merck & Co., Inc. , Boston, Massachusetts, USA.
  • Warrass R; Merck & Co., Inc. , West Point, Pennsylvania, USA.
  • Dick T; MSD Animal Health Innovation GmbH, Zur Propstei , Schwabenheim, Germany.
Antimicrob Agents Chemother ; 68(1): e0071723, 2024 Jan 10.
Article en En | MEDLINE | ID: mdl-38018963
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.
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Texto completo: 1 Base de datos: MEDLINE Asunto principal: Antagonistas del Ácido Fólico / Mycobacterium abscessus / Infecciones por Mycobacterium no Tuberculosas / Mycobacterium tuberculosis Idioma: En Revista: Antimicrob Agents Chemother Año: 2024 Tipo del documento: Article

Texto completo: 1 Base de datos: MEDLINE Asunto principal: Antagonistas del Ácido Fólico / Mycobacterium abscessus / Infecciones por Mycobacterium no Tuberculosas / Mycobacterium tuberculosis Idioma: En Revista: Antimicrob Agents Chemother Año: 2024 Tipo del documento: Article