Tailored phenyl ureas eradicate drug-resistant Mycobacterium tuberculosis by targeting mycolic acid cell wall assembly

Abstract

Treatment of Mycobacterium tuberculosis infections is a challenging task due to long treatment regiments and a growing number of resistant clinical isolates. To identify new antibiotic hits, we screened a focused library of 400 synthetic compounds derived from a recently discovered molecule with promising anti-mycobacterial activity. A suite of more potent hit molecules was deciphered with sub-micromolar activity. Utilising tailored affinity-based probes for chemical proteomic investigations, we successfully pinpointed the mycolic acid transporter MmpL3 and two epoxide hydrolases, EphD and EphF, also linked to mycolic acid biosynthesis, as specific targets of the compounds. These targets were thoroughly and independently validated by activity assays, under- and overexpression, resistance generation, and proteomic studies. Structural refinement of the most potent hit molecules led to the development of a new lead compound that demonstrates enhanced biological activity in M. tuberculosis, low human cytotoxicity, and improved solubility and oral bioavailability – traits that are often challenging to achieve with anti-mycobacterial drugs. Overall, drug-likeness, as well as the dual mode of action, addressing the mycolic acid cell wall assembly at two distinct steps, holds significant potential for further in vivo applications.

Graphical abstract: Tailored phenyl ureas eradicate drug-resistant Mycobacterium tuberculosis by targeting mycolic acid cell wall assembly

Supplementary files

Article information

Article type
Edge Article
Submitted
06 Apr 2025
Accepted
14 Apr 2025
First published
30 Apr 2025
This article is Open Access

All publication charges for this article have been paid for by the Royal Society of Chemistry
Creative Commons BY license

Chem. Sci., 2025, Advance Article

Tailored phenyl ureas eradicate drug-resistant Mycobacterium tuberculosis by targeting mycolic acid cell wall assembly

D. Mostert, J. Braun, M. D. Zimmerman, C. A. Engelhart, S. Berndl, P. K. Quoika, A. M. Kany, J. Proietto, S. Penalva-Lopez, J. B. Wallach, A. K. H. Hirsch, M. Zacharias, D. Schnappinger, V. Dartois and S. A. Sieber, Chem. Sci., 2025, Advance Article , DOI: 10.1039/D5SC02565F

This article is licensed under a Creative Commons Attribution 3.0 Unported Licence. You can use material from this article in other publications without requesting further permissions from the RSC, provided that the correct acknowledgement is given.

Read more about how to correctly acknowledge RSC content.

Social activity

Spotlight

Advertisements