{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T04:55:41Z","timestamp":1790916941073,"version":"4.1.0"},"reference-count":36,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T00:00:00Z","timestamp":1790899200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Tuberc."],"abstract":"<jats:p>\n                    In 2023, tuberculosis (TB) once again became the world's deadliest infectious disease, overtaking COVID-19 as the leading cause of death from a single infectious agent, Mycobacterium tuberculosis (MTB). The World Health Organization (WHO) reports that the COVID-19 pandemic has reversed years of progress in providing essential TB services and reducing TB disease burden. In 2025, TB was responsible for an estimated 1.23 million deaths globally (95% uncertainty interval: 1.13\u20131.33 million), and there were 400\u2005K cases of rifamycin resistant\/multidrug resistant TB (RR, RIFR, MDR). While treatment success for drug susceptible TB remains high (88%), outcomes for MDR\/RR-TB are lower but improving, reaching 71% globally. Clearly, there is a critical unmet need for novel antibiotics against MTB, exacerbated now due to COVID-19. The limited success in pursuing novel targets underscores the urgent need to revisit and reevaluate the mechanisms of action behind existing and once effective drugs, a strategy that may hold untapped potential in the fight against growing antibiotic-resistant TB. The MTB RNA polymerase (RNAP) is a proven target for TB treatment by rifampin (RMP), which kills both active and latent MTB. However, RMP suffers from several drawbacks including: long treatment times, activation of hPXR (inducing Cyp3A4 which is problematic for HIV-TB coinfection), and resistant mutations within RNAP. Two newer treatments with novel mechanisms of action include bedaquiline and delamanid, the former has been approved by the FDA for the treatment of multiple-drug resistant tuberculosis (MDR-MTB); however, even these new drugs already have incidences of acquired resistance. Our\n                    <jats:italic>goal<\/jats:italic>\n                    is to develop novel drug candidates for TB treatment that: target RNAP, have the potential to shorten treatment times, and have activity against RIF\n                    <jats:sup>R<\/jats:sup>\n                    mutants. Our approach, orthogonal to the rifamycins, is to target the interaction of MTB RNAP with the required transcription factor CarD. We have previously labeled CarD with the BODIPY-FL fluorophore via engineered cysteine mutations and developed a fluorescence polarization assay to monitor its interaction with RNAP and promoter DNA. Leveraging this target, we screened a 24\u2005K small molecule library against CarD binding to MTB RNAP. We have now extended this screening to\u223c88,000 additional molecules.\n                  <\/jats:p>","DOI":"10.3389\/ftubr.2026.1937953","type":"journal-article","created":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T04:41:27Z","timestamp":1790916087000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["High-throughput screening to identify inhibitors of the MTB CARD\u2022RNA polymerase protein-protein interaction"],"prefix":"10.3389","volume":"4","author":[{"given":"Glory M.","family":"Velazquez","sequence":"first","affiliation":[{"name":"Department of Medicinal Chemistry, University of Michigan","place":["Ann Arbor, MI, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan Z.","family":"Sexton","sequence":"additional","affiliation":[{"name":"Department of Medicinal Chemistry, University of Michigan","place":["Ann Arbor, MI, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Scott G.","family":"Franzblau","sequence":"additional","affiliation":[{"name":"Institute for Tuberculosis Research, University of Illinois","place":["Chicago, IL, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gauri S.","family":"Shetye","sequence":"additional","affiliation":[{"name":"Institute for Tuberculosis Research, University of Illinois","place":["Chicago, IL, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akil","family":"Hossain","sequence":"additional","affiliation":[{"name":"Institute for Tuberculosis Research, University of Illinois","place":["Chicago, IL, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"George A.","family":"Garcia","sequence":"additional","affiliation":[{"name":"Department of Medicinal Chemistry, University of Michigan","place":["Ann Arbor, MI, United 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