{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,5]],"date-time":"2026-08-05T02:41:49Z","timestamp":1785897709504,"version":"3.56.0"},"reference-count":46,"publisher":"Oxford University Press (OUP)","issue":"1","license":[{"start":{"date-parts":[[2024,12,29]],"date-time":"2024-12-29T00:00:00Z","timestamp":1735430400000},"content-version":"vor","delay-in-days":1,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/100006221","name":"United States\u2013Israel Binational Science Foundation","doi-asserted-by":"publisher","award":["2016142"],"award-info":[{"award-number":["2016142"]}],"id":[{"id":"10.13039\/100006221","id-type":"DOI","asserted-by":"publisher"}]},{"name":"IMTI"},{"name":"Israel Ministry of Industry","award":["59081"],"award-info":[{"award-number":["59081"]}]},{"DOI":"10.13039\/501100003977","name":"Israel Science Foundation","doi-asserted-by":"publisher","award":["1023\/18"],"award-info":[{"award-number":["1023\/18"]}],"id":[{"id":"10.13039\/501100003977","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,1,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Tuberculosis is a major cause of mortality worldwide, with drug-resistant strains complicating its treatment. We report the discovery of small-molecule inhibitors targeting the gyrase of Mycobacterium tuberculosis, the bacterium responsible for tuberculosis. Gyrase, a type II topoisomerase, consists of two subunits: GyrA, which breaks and rejoins DNA, and GyrB, which contains the ATPase domain responsible for ATP binding and hydrolysis. An indole scaffold identified by nuclear magnetic resonance fragment screening was grown into drug-sized candidates through computational optimization, chemical synthesis and functional selection. Several indole-containing gyrase inhibitors were found to be specific for the GyrB subunit of M. tuberculosis. Structural studies using double electron\u2013electron resonance spectroscopy between the Mn(II) ion in the catalytic site of GyrB and a nitroxide-labeled inhibitor provided insights into the potential docking sites of the protein target. Key chemical descriptors essential for gyrase binding were identified for the small-molecule inhibitors using data-driven algorithms. Our results demonstrate the effectiveness of fragment screening and computational optimization in drug discovery. The inhibitors presented in this study are promising candidates for further pharmacological studies in vivo.<\/jats:p>","DOI":"10.1093\/narmme\/ugae027","type":"journal-article","created":{"date-parts":[[2024,12,29]],"date-time":"2024-12-29T03:23:47Z","timestamp":1735442627000},"source":"Crossref","is-referenced-by-count":3,"title":["Indole-containing inhibitors with improved efficacy targeting the gyrase of <i>Mycobacterium tuberculosis<\/i>"],"prefix":"10.1093","volume":"2","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7699-3086","authenticated-orcid":false,"given":"Shankar","family":"Bhattarai","sequence":"first","affiliation":[{"name":"Department of Chemistry, Ben-Gurion University of the Negev , David Ben-Gurion Blvd. 1, Beer-Sheva 8410501 P.O Box 653,","place":["Israel"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vinay Shankar","family":"Tiwari","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Ben-Gurion University of the Negev , David Ben-Gurion Blvd. 1, Beer-Sheva 8410501 P.O Box 653,","place":["Israel"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benjamin","family":"Tam","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Ben-Gurion University of the Negev , David Ben-Gurion Blvd. 1, Beer-Sheva 8410501 P.O Box 653,","place":["Israel"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aviv","family":"Rozen","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Ben-Gurion University of the Negev , David Ben-Gurion Blvd. 1, Beer-Sheva 8410501 P.O Box 653,","place":["Israel"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adam","family":"Soffer","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Ben-Gurion University of the Negev , David Ben-Gurion Blvd. 1, Beer-Sheva 8410501 P.O Box 653,","place":["Israel"]},{"name":"Data Science Research Center, Ben-Gurion University of the Negev ,\u00a0David Ben-Gurion Blvd. 1, Beer-Sheva 8410501 P.O Box 653,","place":["Israel"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samuel","family":"Durbah","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Ben-Gurion University of the Negev , David Ben-Gurion Blvd. 1, Beer-Sheva 8410501 P.O Box 653,","place":["Israel"]},{"name":"Data Science Research Center, Ben-Gurion University of the Negev ,\u00a0David Ben-Gurion Blvd. 1, Beer-Sheva 8410501 P.O Box 653,","place":["Israel"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah Adi","family":"Eisdorfer","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Ben-Gurion University of the Negev , David Ben-Gurion Blvd. 1, Beer-Sheva 8410501 P.O Box 653,","place":["Israel"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angeliki","family":"Giannoulis","sequence":"additional","affiliation":[{"name":"Department of Chemical and Biological Physics, Weizmann Institute of Science , 234 Herzl St. Rehovot 7610001,","place":["Israel"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniella","family":"Goldfarb","sequence":"additional","affiliation":[{"name":"Department of Chemical and Biological Physics, Weizmann Institute of Science , 234 Herzl St. Rehovot 7610001,","place":["Israel"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3882-2742","authenticated-orcid":false,"given":"Barak","family":"Akabayov","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Ben-Gurion University of the Negev , David Ben-Gurion Blvd. 1, Beer-Sheva 8410501 P.O Box 653,","place":["Israel"]},{"name":"Data Science Research Center, Ben-Gurion University of the Negev ,\u00a0David Ben-Gurion Blvd. 1, Beer-Sheva 8410501 P.O Box 653,","place":["Israel"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2024,12,28]]},"reference":[{"key":"2025032916275668300_B1","doi-asserted-by":"crossref","first-page":"2003300","DOI":"10.1183\/13993003.03300-2020","article-title":"World Health Organization recommendations on the treatment of drug-resistant tuberculosis, 2020 update","volume":"57","author":"Mirzayev","year":"2021","journal-title":"Eur. Respir. J."},{"key":"2025032916275668300_B2","doi-asserted-by":"crossref","first-page":"388","DOI":"10.1038\/nrd4001","article-title":"Advances in the development of new tuberculosis drugs and treatment regimens","volume":"12","author":"Zumla","year":"2013","journal-title":"Nat. Rev. Drug Discov."},{"key":"2025032916275668300_B3","doi-asserted-by":"crossref","first-page":"291","DOI":"10.1016\/S2213-2600(17)30079-6","article-title":"The epidemiology, pathogenesis, transmission, diagnosis, and management of multidrug-resistant, extensively drug-resistant, and incurable tuberculosis","volume":"5","author":"Dheda","year":"2017","journal-title":"Lancet Respir. Med."},{"key":"2025032916275668300_B4","doi-asserted-by":"crossref","first-page":"645","DOI":"10.5588\/ijtld.18.0622","article-title":"Management of patients with multidrug-resistant tuberculosis","volume":"23","author":"Lange","year":"2019","journal-title":"Int. J. Tuberc. 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