TY - JOUR
T1 - Azetidines Kill Multidrug-Resistant Mycobacterium tuberculosis without Detectable Resistance by Blocking Mycolate Assembly
AU - Cui, Yixin
AU - Lanne, Alice
AU - Peng, Xudan
AU - Browne, Edward
AU - Bhatt, Apoorva
AU - Coltman, Nicholas J.
AU - Craven, Philip
AU - Cox, Liam R.
AU - Cundy, Nicholas J.
AU - Dale, Katie
AU - Feula, Antonio
AU - Frampton, Jon
AU - Fung, Martin
AU - Morton, Michael
AU - Goff, Aaron
AU - Salih, Mariwan
AU - Lang, Xingfen
AU - Li, Xingjian
AU - Moon, Chris
AU - Pascoe, Jordan
AU - Portman, Vanessa
AU - Press, Cara
AU - Schulz-Utermoehl, Timothy
AU - Lee, Suki
AU - Tortorella, Micky D.
AU - Tu, Zhengchao
AU - Underwood, Zoe E.
AU - Wang, Changwei
AU - Yoshizawa, Akina
AU - Zhang, Tianyu
AU - Waddell, Simon J.
AU - Bacon, Joanna
AU - Alderwick, Luke
AU - Fossey, John S.
AU - Neagoie, Cleopatra
N1 - Publisher Copyright:
© 2024 The Authors. Published by American Chemical Society
PY - 2024/2/22
Y1 - 2024/2/22
N2 - 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 MIC99 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.
AB - 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 MIC99 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.
UR - http://www.scopus.com/inward/record.url?scp=85185706205&partnerID=8YFLogxK
UR - https://www.mendeley.com/catalogue/03cf4dba-c569-334b-a579-e746b03ee53c/
U2 - 10.1021/acs.jmedchem.3c01643
DO - 10.1021/acs.jmedchem.3c01643
M3 - Article
C2 - 38331432
AN - SCOPUS:85185706205
SN - 0022-2623
VL - 67
SP - 2529
EP - 2548
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 4
ER -
