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Current antibiotic regimens for the treatment of TB remain dated and suffer from long treatment times as well as the development of drug resistance. As such, the search for novel chemical modalities that have selective or potent anti-Mtb properties remains an urgent priority, particularly against multidrug-resistant (MDR) Mtb strains. Herein, we design and synthesize 35 novel\n                      <jats:underline>b<\/jats:underline>\n                      enzo[c]\n                      <jats:underline>p<\/jats:underline>\n                      henanthridine\n                      <jats:underline>d<\/jats:underline>\n                      erivatives (BPDs). The two most potent compounds, BPD-6 and BPD-9, accumulated within the bacterial cell and exhibited strong inhibitory activity (MIC\n                      <jats:sub>90<\/jats:sub>\n                      ~2 to 10 \u00b5M) against multiple\n                      <jats:italic>Mycobacterium<\/jats:italic>\n                      strains while remaining inactive against a range of other Gram-negative and Gram-positive bacteria. BPD-6 and BPD-9 were also effective in reducing Mtb survival within infected macrophages, and BPD-9 reduced the burden of\n                      <jats:italic>Mycobacterium bovis<\/jats:italic>\n                      BCG in the lungs of infected mice. The two BPD compounds displayed comparable efficacy to rifampicin (RIF) against non-replicating Mtb (NR-Mtb). Importantly, BPD-6 and BPD-9 inhibited the growth of multiple MDR Mtb clinical isolates. Generation of BPD-9-resistant mutants identified the involvement of the Mmr efflux pump as an indirect resistance mechanism. The unique specificity of BPDs to\n                      <jats:italic>Mycobacterium<\/jats:italic>\n                      spp. and their efficacy against MDR Mtb isolates suggest a potential novel mechanism of action. The discovery of BPDs provides novel chemical scaffolds for anti-TB drug discovery.\n                    <\/jats:p>\n                    <jats:sec>\n                      <jats:title>IMPORTANCE<\/jats:title>\n                      <jats:p>\n                        The emergence of drug-resistant tuberculosis (TB) is a serious global health threat. There remains an urgent need to discover new antibiotics with unique mechanisms of action that are effective against drug-resistant\n                        <jats:italic>Mycobacterium tuberculosis<\/jats:italic>\n                        (Mtb). This study shows that novel semi-synthetic compounds can be derived from natural compounds to produce potent activity against Mtb. Importantly, the identified compounds have narrow spectrum activity against\n                        <jats:italic>Mycobacterium<\/jats:italic>\n                        species, including clinical multidrug-resistant (MDR) strains, are effective in infected macrophages and against non-replicating Mtb (NR-Mtb), and show anti-mycobacterial activity in mice. These new compounds provide promising chemical scaffolds to develop potent anti-Mtb drugs of the future.\n                      <\/jats:p>\n                    <\/jats:sec>\n                  <\/jats:sec>","DOI":"10.1128\/spectrum.01246-24","type":"journal-article","created":{"date-parts":[[2024,10,3]],"date-time":"2024-10-03T15:18:54Z","timestamp":1727968734000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":3,"title":["Discovery of benzo[c]phenanthridine derivatives with potent activity against multidrug-resistant\n                    <i>Mycobacterium tuberculosis<\/i>"],"prefix":"10.1128","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0797-126X","authenticated-orcid":true,"given":"Yi Chu","family":"Liang","sequence":"first","affiliation":[{"name":"Department of Microbiology and Immunology, University of British Columbia, Vancouver, Canada"},{"name":"Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhiqi","family":"Sun","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chen","family":"Lu","sequence":"additional","affiliation":[{"name":"Chinese Academy of Sciences Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences, Shanghai, China"},{"name":"University of Chinese Academy of Sciences, Beijing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andr\u00e9anne","family":"Lupien","sequence":"additional","affiliation":[{"name":"Infectious Diseases and Immunity in Global Health Program, Research Institute of the McGill University Health Centre, Montr\u00e9al, Canada"},{"name":"McGill International TB Centre, Montr\u00e9al, Canada"},{"name":"Department of Microbiology and Immunology, McGill University, Montr\u00e9al, Canada"},{"name":"Department of Medicine, McGill University Health Centre, Montr\u00e9al, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhongliang","family":"Xu","sequence":"additional","affiliation":[{"name":"Chinese Academy of Sciences Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences, Shanghai, China"},{"name":"University of Chinese Academy of Sciences, Beijing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2961-6100","authenticated-orcid":false,"given":"Stefania","family":"Berton","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, 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