Azetidines Kill Multidrug-Resistant Without Detectable Resistance by Blocking Mycolate Assembly

Overview

Journal J Med Chem

Publisher American Chemical Society

Specialty Chemistry

Date 2024 Feb 8

PMID 38331432

Authors

Yixin Cui

Alice Lanne

Xudan Peng

Edward Browne

Apoorva Bhatt

Nicholas J Coltman

Philip Craven

Liam R Cox

Nicholas J Cundy

Katie Dale

Antonio Feula

Jon Frampton

Martin Fung

Michael Morton

Aaron Goff

Mariwan Salih

Xingfen Lang

Xingjian Li

Chris Moon

Jordan Pascoe

Vanessa Portman

Cara Press

Timothy Schulz-Utermoehl

Suki Lee

Micky D Tortorella

Zhengchao Tu

Zoe E Underwood

Changwei Wang

Akina Yoshizawa

Tianyu Zhang

Simon J Waddell

Joanna Bacon

Luke Alderwick

John S Fossey

Cleopatra Neagoie

Affiliations

Soon will be listed here.

Abstract

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 values <10 μM against drug-sensitive 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.

Citing Articles

Densely Functionalized 2-Methylideneazetidines: Evaluation as Antibacterials.

Petrillo G, Tavani C, Bianchi L, Benzi A, Cavalluzzi M, Salvagno L Molecules. 2021; 26(13).

PMID: 34202191 PMC: 8271477. DOI: 10.3390/molecules26133891.

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