SuFEx-based antitubercular compound irreversibly inhibits Pks13

Area of Science:

• Medicinal Chemistry
• Microbiology
• Drug Discovery

Background:

• Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), is a leading global infectious disease.
• Existing TB treatments require long durations and face challenges from multi-drug-resistant (MDR) and extensively drug-resistant (XDR) strains.
• Novel therapeutic strategies targeting essential Mtb pathways are urgently needed to shorten treatment and overcome resistance.

Purpose of the Study:

• To introduce CMX410, a novel preclinical covalent compound targeting Pks13.
• To evaluate the efficacy and mechanism of action of CMX410 against Mtb.
• To assess the safety and pharmacological profile of CMX410.

Main Methods:

• CMX410 was designed as an aryl fluorosulfate (SuFEx) covalent inhibitor.
• The compound's activity was tested against drug-sensitive and drug-resistant Mtb strains in vitro.
• Efficacy was assessed in mouse models of Mtb infection.
• The mechanism of inhibition involved targeting the Pks13 acyltransferase domain.
• Pharmacological and safety profiles were evaluated, including a rat toxicity study.

Main Results:

• CMX410 demonstrated equipotent activity against both drug-sensitive and drug-resistant Mtb strains.
• The compound was efficacious in multiple mouse models of Mtb infection.
• CMX410 irreversibly inhibits Pks13 by forming a beta-lactam with the catalytic serine in the acyltransferase domain.
• CMX410 exhibited high target selectivity and excellent pharmacological and safety profiles, with no adverse effects in rats at high doses.
• CMX410 showed favorable performance in drug combination testing.

Conclusions:

• CMX410 represents a promising first-in-class drug candidate for tuberculosis treatment.
• Its unique mechanism of action and favorable profile offer a potential replacement for current cell-wall biosynthesis inhibitors.
• CMX410's potency, safety, and oral bioavailability support its advancement in TB drug development.