{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,4]],"date-time":"2025-10-04T07:36:19Z","timestamp":1759563379839},"reference-count":43,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2015,4,2]],"date-time":"2015-04-02T00:00:00Z","timestamp":1427932800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"name":"Aurigene Discovery Technologies Ltd"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Protein Science"],"published-print":{"date-parts":[[2015,5]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Melioidosis is a tropical bacterial infection caused by<jats:italic>Burkholderia pseudomallei<\/jats:italic>(<jats:italic>B. pseudomallei<\/jats:italic>; Bpm), a Gram\u2010negative bacterium. Current therapeutic options are largely limited to trimethoprim\u2010sulfamethoxazole and \u03b2\u2010lactam drugs, and the treatment duration is about 4 months. Moreover, resistance has been reported to these drugs. Hence, there is a pressing need to develop new antibiotics for Melioidosis. Inhibition of enoyl\u2010ACP reducatase (FabI), a key enzyme in the fatty acid biosynthesis pathway has shown significant promise for antibacterial drug development. FabI has been identified as the major enoyl\u2010ACP reductase present in<jats:italic>B. pseudomallei<\/jats:italic>. In this study, we evaluated AFN\u20101252, a<jats:italic>Staphylococcus aureus<\/jats:italic>FabI inhibitor currently in clinical development, for its potential to bind to BpmFabI enzyme and inhibit<jats:italic>B. pseudomallei<\/jats:italic>bacterial growth. AFN\u20101252 stabilized BpmFabI and inhibited the enzyme activity with an IC<jats:sub>50<\/jats:sub>of 9.6 nM. It showed good antibacterial activity against<jats:italic>B. pseudomallei<\/jats:italic>R15 strain, isolated from a melioidosis patient (MIC of 2.35 mg\/L). X\u2010ray structure of BpmFabI with AFN\u20101252 was determined at a resolution of 2.3 \u00c5. Complex of BpmFabI with AFN\u20101252 formed a symmetrical tetrameric structure with one molecule of AFN\u20101252 bound to each monomeric subunit. The kinetic and thermal melting studies supported the finding that AFN\u20101252 can bind to BpmFabI independent of cofactor. The structural and mechanistic insights from these studies might help the rational design and development of new FabI inhibitors.<\/jats:p>","DOI":"10.1002\/pro.2655","type":"journal-article","created":{"date-parts":[[2015,2,2]],"date-time":"2015-02-02T20:22:51Z","timestamp":1422908571000},"page":"832-840","source":"Crossref","is-referenced-by-count":12,"title":["<scp>AFN<\/scp>\u20101252 is a potent inhibitor of enoyl\u2010<scp>ACP<\/scp>reductase from<scp><i>B<\/i><\/scp><i>urkholderia pseudomallei<\/i>\u2014Crystal structure, mode of action, and biological activity"],"prefix":"10.1002","volume":"24","author":[{"given":"Krishnamurthy","family":"Narasimha Rao","sequence":"first","affiliation":[{"name":"Aurigene Discovery Technologies Ltd, 39\u201040, KIADB Industrial area, Electronic city Phase II Hosur Road Bangalore 560 100 India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anirudha","family":"Lakshminarasimhan","sequence":"additional","affiliation":[{"name":"Aurigene Discovery Technologies Ltd, 39\u201040, KIADB Industrial area, Electronic city Phase II Hosur Road Bangalore 560 100 India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sarah","family":"Joseph","sequence":"additional","affiliation":[{"name":"Aurigene Discovery Technologies Ltd, 39\u201040, KIADB Industrial area, Electronic city Phase II Hosur Road Bangalore 560 100 India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Swathi U.","family":"Lekshmi","sequence":"additional","affiliation":[{"name":"Aurigene Discovery Technologies Ltd, 39\u201040, KIADB Industrial area, Electronic city Phase II Hosur Road Bangalore 560 100 India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ming\u2010Seong","family":"Lau","sequence":"additional","affiliation":[{"name":"School of Biosciences and Biotechnology, Faculty of Science and Technology, Universiti Kebangsaan Malaysia 43600 Bangi Selangor Malaysia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mohammed","family":"Takhi","sequence":"additional","affiliation":[{"name":"Aurigene Discovery Technologies Ltd Bollaram Road, Miyapur Hyderabad 500 049 India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kandepu","family":"Sreenivas","sequence":"additional","affiliation":[{"name":"Aurigene Discovery Technologies Ltd Bollaram Road, Miyapur Hyderabad 500 049 India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sheila","family":"Nathan","sequence":"additional","affiliation":[{"name":"School of Biosciences and Biotechnology, Faculty of Science and Technology, Universiti Kebangsaan Malaysia 43600 Bangi Selangor Malaysia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rohana","family":"Yusof","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine Faculty of Medicine, University of Malaya 50603 Kuala Lumpur Malaysia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Noorsaadah","family":"Abd. 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