Novel chemical entities inhibiting Mycobacterium tuberculosis growth identified by phenotypic high-throughput screening
oleh: Anuradha Kumar, Somsundaram Chettiar, Brian S. Brown, Julie Early, Juliane Ollinger, Megan Files, Mai A. Bailey, Aaron Korkegian, Devon Dennison, Matthew McNeil, James Metz, Augustine Osuma, Michael Curtin, Aaron Kunzer, Gail Freiberg, Milan Bruncko, Dale Kempf, Tanya Parish
| Format: | Article |
|---|---|
| Diterbitkan: | Nature Portfolio 2022-09-01 |
Deskripsi
Abstract We performed a high-throughput phenotypic whole cell screen of Mycobacterium tuberculosis against a diverse chemical library of approximately 100,000 compounds from the AbbVie corporate collection and identified 24 chemotypes with anti-tubercular activity. We selected two series for further exploration and conducted structure–activity relationship studies with new analogs for the 4-phenyl piperidines (4PP) and phenylcyclobutane carboxamides (PCB). Strains with mutations in MmpL3 demonstrated resistance to both compound series. We isolated resistant mutants for the two series and found mutations in MmpL3. These data suggest that MmpL3 is the target, or mechanism of resistance for both series.