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One potential target for drug development against pathogenic mycobacteria is their need to degrade host cholesterol during infection.\n                      <jats:italic toggle=\"yes\">Mycobacterium leprae<\/jats:italic>\n                      , due to its degenerate genome, has preserved only the first step of cholesterol catabolism, in which cholesterol is oxidized to cholestenone by the enzyme 3\u03b2-hydroxysteroid dehydrogenase (3\u03b2-HSD).\n                      <jats:italic toggle=\"yes\">M. leprae<\/jats:italic>\n                      avidly produces cholestenone\n                      <jats:italic toggle=\"yes\">in vivo,<\/jats:italic>\n                      and this metabolic activity seems to play an important role in bacterial pathogenesis. In this study, six 6-azasteroid analogs were developed with the potential to inhibit 3\u03b2-HSD, and their metabolic stability and\n                      <jats:italic toggle=\"yes\">in vitro<\/jats:italic>\n                      and\n                      <jats:italic toggle=\"yes\">in vivo<\/jats:italic>\n                      inhibitory activity against\n                      <jats:italic toggle=\"yes\">M. leprae<\/jats:italic>\n                      were investigated. Pharmacologic properties indicated lower metabolic liabilities for azasteroid\n                      <jats:bold>5<\/jats:bold>\n                      in comparison to its progenitors, azasteroids\n                      <jats:bold>1<\/jats:bold>\n                      and\n                      <jats:bold>2,<\/jats:bold>\n                      resulting in improved accumulation and extended\n                      <jats:italic toggle=\"yes\">t<\/jats:italic>\n                      <jats:sub>1\/2<\/jats:sub>\n                      values in mice. Azasteroid\n                      <jats:bold>5<\/jats:bold>\n                      also partially inhibits\n                      <jats:italic toggle=\"yes\">M. leprae<\/jats:italic>\n                      3\u03b2-HSD\n                      <jats:italic toggle=\"yes\">in vitro<\/jats:italic>\n                      . When tested in the Shepard\u2019s mouse footpad model of leprosy, azasteroid\n                      <jats:bold>5<\/jats:bold>\n                      showed effective bacterial killing that was accelerated when combined with a subinhibitory dose of rifampicin and exhibited an absence of detectable hepatotoxic effects. We concluded that 6-azasteroids derivatives are promising new antimicrobial candidates for leprosy treatment.\n                    <\/jats:p>\n                    <jats:sec>\n                      <jats:title>IMPORTANCE<\/jats:title>\n                      <jats:p>\n                        Leprosy remains a significant global health challenge, particularly in underserved regions. While multidrug therapy (MDT) has been effective, its prolonged duration and the emergence of antibiotic-resistant strains emphasize the urgent need for novel therapeutic strategies. Recent advances in understanding\n                        <jats:italic toggle=\"yes\">Mycobacterium leprae<\/jats:italic>\n                        \u2019s unique biology have identified cholesterol metabolism as a critical pathway for bacterial survival and pathogenesis, offering a promising new target for drug development. Building on insights from tuberculosis research, azasteroids\u2014compounds known for their potential to disrupt mycobacterial cholesterol metabolism\u2014are now being explored as candidates for leprosy treatment. These molecules inhibit\n                        <jats:italic toggle=\"yes\">M. leprae<\/jats:italic>\n                        \u2019s cholesterol oxidation, impairing bacterial persistence within the host. This innovative approach could lead to more effective, faster-acting therapies, overcoming current treatment limitations and resistance. Such efforts represent a vital step forward in reducing the burden of leprosy and empowering affected communities worldwide.\n                      <\/jats:p>\n                    <\/jats:sec>\n                  <\/jats:sec>","DOI":"10.1128\/spectrum.00228-25","type":"journal-article","created":{"date-parts":[[2025,5,27]],"date-time":"2025-05-27T09:02:12Z","timestamp":1748336532000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":1,"title":["Pharmacologic properties and inhibitory activity of 6-azasteroids against\n                    <i>Mycobacterium leprae in vivo<\/i>\n                    and\n                    <i>in vitro<\/i>"],"prefix":"10.1128","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4866-8021","authenticated-orcid":false,"given":"Thabatta","family":"L. S. A. 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