A multi-targeting pre-clinical candidate against drug-resistant tuberculosis

Area of Science:

• Medicinal Chemistry
• Microbiology
• Pharmacology

Background:

• Tuberculosis (TB) remains a significant global health challenge, particularly drug-resistant strains.
• Novel therapeutic agents are urgently needed to combat multidrug-resistant tuberculosis (MDR-TB).

Purpose of the Study:

• To evaluate FNDR-20081 as a novel, first-in-class anti-tubercular pre-clinical candidate.
• To assess the efficacy and safety profile of FNDR-20081 against Mycobacterium tuberculosis (Mtb).

Main Methods:

• In vitro studies assessing FNDR-20081's activity against replicating and non-replicating Mtb.
• Combination studies with existing anti-TB drugs.
• In vivo efficacy testing in a mouse model of Mtb infection.
• Whole genome sequencing (WGS) to identify resistance mechanisms.

Main Results:

• FNDR-20081 demonstrated potent activity against both sensitive and drug-resistant Mtb strains.
• No antagonism was observed when FNDR-20081 was combined with first- and second-line anti-TB drugs.
• The compound exhibited dose-dependent killing of Mtb and efficacy in a mouse infection model.
• WGS identified marR (Rv0678) and Rv3683 as potential targets involved in FNDR-20081 resistance.

Conclusions:

• FNDR-20081 is a promising pre-clinical candidate for treating MDR-TB.
• Its non-toxic profile and compatibility with existing drugs support its potential in new combination regimens.