{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T03:38:18Z","timestamp":1791257898388,"version":"4.1.0"},"reference-count":41,"publisher":"American Society for Microbiology","issue":"1","license":[{"start":{"date-parts":[[2024,1,10]],"date-time":"2024-01-10T00:00:00Z","timestamp":1704844800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2024,1,10]],"date-time":"2024-01-10T00:00:00Z","timestamp":1704844800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"funder":[{"name":"HHS | National Institutes of Health","award":["R01AI132374"],"award-info":[{"award-number":["R01AI132374"]}]}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["Antimicrob Agents Chemother"],"published-print":{"date-parts":[[2024,1,10]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n          <jats:p>\n            The\n            <jats:italic>Mycobacterium abscessus<\/jats:italic>\n            drug development pipeline is poorly populated, with particularly few validated target-lead couples to initiate\n            <jats:italic>de novo<\/jats:italic>\n            drug discovery. Trimethoprim, an inhibitor of dihydrofolate reductase (DHFR) used for the treatment of a range of bacterial infections, is not active against\n            <jats:italic>M. abscessus<\/jats:italic>\n            . Thus, evidence that\n            <jats:italic>M. abscessus<\/jats:italic>\n            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\n            <jats:italic>Mycobacterium tuberculosis<\/jats:italic>\n            , exerts whole cell activity against\n            <jats:italic>M. abscessus<\/jats:italic>\n            . Enzyme inhibition studies showed that PQD-1, in contrast to trimethoprim, is a potent inhibitor of\n            <jats:italic>M. abscessus<\/jats:italic>\n            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\u2019s growth inhibitory activity in\n            <jats:italic>M. abscessus<\/jats:italic>\n            . As observed in\n            <jats:italic>M. tuberculosis<\/jats:italic>\n            , 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\n            <jats:italic>M. abscessus<\/jats:italic>\n            . PQD-1 is active against subspecies of\n            <jats:italic>M. abscessus<\/jats:italic>\n            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\n            <jats:italic>M. abscessus<\/jats:italic>\n            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\n            <jats:italic>M. abscessus<\/jats:italic>\n            .\n          <\/jats:p>","DOI":"10.1128\/aac.00717-23","type":"journal-article","created":{"date-parts":[[2023,11,29]],"date-time":"2023-11-29T14:00:16Z","timestamp":1701266416000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":16,"title":["Pharmacological validation of dihydrofolate reductase as a drug target in\n            <i>Mycobacterium abscessus<\/i>"],"prefix":"10.1128","volume":"68","author":[{"given":"Wassihun Wedajo","family":"Aragaw","sequence":"first","affiliation":[{"name":"Center for Discovery and Innovation, Hackensack Meridian Health , Nutley, New Jersey, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dereje A.","family":"Negatu","sequence":"additional","affiliation":[{"name":"Center for Discovery and Innovation, Hackensack Meridian Health , Nutley, New Jersey, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher J.","family":"Bungard","sequence":"additional","affiliation":[{"name":"Merck &amp; Co., Inc. , West Point, Pennsylvania, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9470-5009","authenticated-orcid":true,"given":"V\u00e9ronique A.","family":"Dartois","sequence":"additional","affiliation":[{"name":"Center for Discovery and Innovation, Hackensack Meridian Health , Nutley, New Jersey, USA"},{"name":"Department of Medical Sciences, Hackensack Meridian School of Medicine , Nutley, New Jersey, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abdellatif 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