Azetidines kill Mycobacterium tuberculosis without detectable resistance by blocking mycolate assembly.
Lanne, A. B.; Cui, Y.; Browne, E.; Craven, P. G. E.; Cundy, N. J.; Coltman, N. J.; Dale, K.; Feula, A.; Frampton, J.; Goff, A.; Hama Salih, M. A.; Lang, X.; Li, X.; Moon, C. W.; Morton, M.; Pascoe, J.; Peng, X.; Portman, V.; Press, C.; Schulz-Utermoehl, T.; Tortorella, M.; Tu, Z.; Underwood, Z. E.; Wang, C.; Yoshizawa, A.; Zhang, T.; Waddell, S. J.; Bacon, J.; Neagoie, C.; Fossey, J. S.; Alderwick, L. J.
Show abstract
Tuberculosis (TB) is the leading cause of global morbidity and mortality resulting from infectious disease, with over 10 million new cases and 1.5 million deaths in 2019. This global emergency is exacerbated by the emergence of multi-drug-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, that elicit potent bactericidal activity with MIC99 values <10 M against drug-sensitive Mycobacterium tuberculosis and MDR-TB were identified. These compounds demonstrate no detectable drug resistance. 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 existing mycobacterial cell-wall inhibitors. In addition, the compounds tested exhibit toxicological and PK/PD profiles that pave the way for their development as anti-tubercular chemotherapies.
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