Azetidines Kill Multidrug-Resistant Mycobacterium tuberculosis without Detectable Resistance by Blocking Mycolate Assembly.

Autor: Cui Y; School of Chemistry, University of Birmingham, Edgbaston, Birmingham, West Midlands B15 2TT, U.K., Lanne A; Institute of Microbiology and Infection, School of Biosciences, University of Birmingham, Edgbaston, Birmingham, West Midlands B15 2TT, U.K., Peng X; State Key Laboratory of Respiratory Disease, China-New Zealand Joint Laboratory on Biomedicine and Health, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Science, 190 Kai Yuan Avenue, Science Park, Guangzhou 510530, China., Browne E; Sygnature Discovery, The Discovery Building, BioCity, Pennyfoot Street, Nottingham NG1 1GR, U.K., Bhatt A; Institute of Microbiology and Infection, School of Biosciences, University of Birmingham, Edgbaston, Birmingham, West Midlands B15 2TT, U.K., Coltman NJ; School of Biosciences, University of Birmingham, Edgbaston, Birmingham, West Midlands B15 2TT, U.K., Craven P; School of Chemistry, University of Birmingham, Edgbaston, Birmingham, West Midlands B15 2TT, U.K., Cox LR; School of Chemistry, University of Birmingham, Edgbaston, Birmingham, West Midlands B15 2TT, U.K., Cundy NJ; School of Chemistry, University of Birmingham, Edgbaston, Birmingham, West Midlands B15 2TT, U.K., Dale K; Institute of Microbiology and Infection, School of Biosciences, University of Birmingham, Edgbaston, Birmingham, West Midlands B15 2TT, U.K., Feula A; School of Chemistry, University of Birmingham, Edgbaston, Birmingham, West Midlands B15 2TT, U.K., Frampton J; College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham, West Midlands B15 2TT, U.K., Fung M; Centre for Regenerative Medicine and Health, Hong Kong Institute of Science & Innovation, Chinese Academy of Sciences, 15 Science Park West Avenue NT, Hong Kong SAR., Morton M; ApconiX Ltd, BIOHUB at Alderly Park, Nether Alderly, Cheshire SK10 4TG, U.K., Goff A; Department of Global Health and Infection, Brighton and Sussex Medical School, University of Sussex, Falmer BN1 9PX, U.K., Salih M; School of Chemistry, University of Birmingham, Edgbaston, Birmingham, West Midlands B15 2TT, U.K., Lang X; State Key Laboratory of Respiratory Disease, China-New Zealand Joint Laboratory on Biomedicine and Health, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Science, 190 Kai Yuan Avenue, Science Park, Guangzhou 510530, China., Li X; School of Chemistry, University of Birmingham, Edgbaston, Birmingham, West Midlands B15 2TT, U.K.; State Key Laboratory of Respiratory Disease, China-New Zealand Joint Laboratory on Biomedicine and Health, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Science, 190 Kai Yuan Avenue, Science Park, Guangzhou 510530, China., Moon C; TB Research Group, National Infection Service, Public Health England (UKHSA), Manor Farm Road, Porton, Salisbury SP4 0JG, U.K., Pascoe J; TB Research Group, National Infection Service, Public Health England (UKHSA), Manor Farm Road, Porton, Salisbury SP4 0JG, U.K., Portman V; Sygnature Discovery, The Discovery Building, BioCity, Pennyfoot Street, Nottingham NG1 1GR, U.K., Press C; Institute of Microbiology and Infection, School of Biosciences, University of Birmingham, Edgbaston, Birmingham, West Midlands B15 2TT, U.K., Schulz-Utermoehl T; Sygnature Discovery, The Discovery Building, BioCity, Pennyfoot Street, Nottingham NG1 1GR, U.K., Lee S; Centre for Regenerative Medicine and Health, Hong Kong Institute of Science & Innovation, Chinese Academy of Sciences, 15 Science Park West Avenue NT, Hong Kong SAR., Tortorella MD; State Key Laboratory of Respiratory Disease, China-New Zealand Joint Laboratory on Biomedicine and Health, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Science, 190 Kai Yuan Avenue, Science Park, Guangzhou 510530, China.; Centre for Regenerative Medicine and Health, Hong Kong Institute of Science & Innovation, Chinese Academy of Sciences, 15 Science Park West Avenue NT, Hong Kong SAR., Tu Z; State Key Laboratory of Respiratory Disease, China-New Zealand Joint Laboratory on Biomedicine and Health, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Science, 190 Kai Yuan Avenue, Science Park, Guangzhou 510530, China., Underwood ZE; TB Research Group, National Infection Service, Public Health England (UKHSA), Manor Farm Road, Porton, Salisbury SP4 0JG, U.K., Wang C; State Key Laboratory of Respiratory Disease, China-New Zealand Joint Laboratory on Biomedicine and Health, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Science, 190 Kai Yuan Avenue, Science Park, Guangzhou 510530, China., Yoshizawa A; School of Chemistry, University of Birmingham, Edgbaston, Birmingham, West Midlands B15 2TT, U.K., Zhang T; State Key Laboratory of Respiratory Disease, China-New Zealand Joint Laboratory on Biomedicine and Health, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Science, 190 Kai Yuan Avenue, Science Park, Guangzhou 510530, China., Waddell SJ; Department of Global Health and Infection, Brighton and Sussex Medical School, University of Sussex, Falmer BN1 9PX, U.K., Bacon J; TB Research Group, National Infection Service, Public Health England (UKHSA), Manor Farm Road, Porton, Salisbury SP4 0JG, U.K., Alderwick L; Institute of Microbiology and Infection, School of Biosciences, University of Birmingham, Edgbaston, Birmingham, West Midlands B15 2TT, U.K.; Discovery Sciences, Charles River Laboratories, Chesterford Research Park, Saffron Walden CB10 1XL, U.K., Fossey JS; School of Chemistry, University of Birmingham, Edgbaston, Birmingham, West Midlands B15 2TT, U.K., Neagoie C; State Key Laboratory of Respiratory Disease, China-New Zealand Joint Laboratory on Biomedicine and Health, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Science, 190 Kai Yuan Avenue, Science Park, Guangzhou 510530, China.; Centre for Regenerative Medicine and Health, Hong Kong Institute of Science & Innovation, Chinese Academy of Sciences, 15 Science Park West Avenue NT, Hong Kong SAR.; Visiting Scientist, School of Chemistry, University of Birmingham, Edgbaston, Birmingham, West Midlands B15 2TT, U.K.
Jazyk: angličtina
Zdroj: Journal of medicinal chemistry [J Med Chem] 2024 Feb 22; Vol. 67 (4), pp. 2529-2548. Date of Electronic Publication: 2024 Feb 08.
DOI: 10.1021/acs.jmedchem.3c01643
Abstrakt: Tuberculosis (TB) is the leading cause of global morbidity and mortality resulting from infectious disease, with over 10.6 million new cases and 1.4 million deaths in 2021. This global emergency is exacerbated by the emergence of multidrug-resistant MDR-TB and extensively drug-resistant XDR-TB; therefore, new drugs and new drug targets are urgently required. From a whole cell phenotypic screen, a series of azetidines derivatives termed BGAz, which elicit potent bactericidal activity with MIC 99 values <10 μM against drug-sensitive Mycobacterium tuberculosis and MDR-TB, were identified. These compounds demonstrate no detectable drug resistance. The mode of action and target deconvolution studies suggest that these compounds inhibit mycobacterial growth by interfering with cell envelope biogenesis, specifically late-stage mycolic acid biosynthesis. Transcriptomic analysis demonstrates that the BGAz compounds tested display a mode of action distinct from the existing mycobacterial cell wall inhibitors. In addition, the compounds tested exhibit toxicological and PK/PD profiles that pave the way for their development as antitubercular chemotherapies.
Databáze: MEDLINE