A New Weapon in the Fight Against Tuberculosis: JSF-3285
- Ray Sullivan
- Jul 22
- 3 min read
Tuberculosis (TB) remains a formidable global health threat, with millions of new cases each year, including a significant proportion that are drug-resistant. The standard treatments for drug-susceptible TB are long, lasting 4 to 6 months, and challenges persist in shortening treatment and improving outcomes. For drug-resistant TB, newer regimens like BPaL (bedaquiline, pretomanid, and linezolid) have emerged, but their clinical use is often hampered by linezolid's toxicity and variable rates of fluoroquinolone resistance. Clearly, there's an urgent need for new, effective, and safer drugs to improve TB treatment options across the board.
Scientists at Rutgers discovered and developed JSF-3285, a promising preclinical candidate that offers a potential breakthrough. This novel compound potently targets Mycobacterium tuberculosis β-ketoacyl-ACP synthase (KasA), an essential enzyme critical for mycolic acid synthesis. Mycolic acids are vital components of the mycobacterial cell wall, and disrupting their synthesis can cripple the bacterium. Because Kas enzymes are essential in bacteria and are not found in mammals, they are potential targets for antibacterial drug development.
Unlike current TB drugs such as isoniazid and ethionamide/prothionamide, which target the downstream enzyme InhA in the fatty acid synthase II pathway, JSF-3285 directly targets KasA, an upstream enzyme. This distinct mechanism of action is key because it means JSF-3285 should retain activity against M. tuberculosis isolates resistant to InhA inhibitors.
Indeed, studies confirmed this vital advantage:
JSF-3285’s minimum inhibitory concentration (MIC) was similar to isoniazid against the standard H37Rv strain.
Crucially, it retained activity against isoniazid-resistant mutants (inhA promoter and katG mutants), whereas isoniazid’s MICs were significantly higher against these resistant strains. This makes JSF-3285 a valuable component for novel regimens treating isoniazid-resistant strains.
While JSF-3285 demonstrated dose-dependent bactericidal effects as a monotherapy in mouse models, significantly reducing bacterial counts at higher doses (10 and 30 mg/kg). Soni, et al., a collaboration between Johns Hopkins, Rutgers, and the Center for Discovery & Innovation, show that its true power shines in combination. JSF-3285 substantially increases the bactericidal activity of the bedaquiline-pretomanid and bedaquiline-pretomanid-linezolid regimens. This leads to a shorter treatment duration needed to prevent relapse in a well-established mouse model of TB.
Here's how JSF-3285 improves these critical regimens:
Regimens combining JSF-3285 with bedaquiline-pretomanid were significantly more active than bedaquiline-pretomanid alone. This additive effect was also observed with combination bedaquiline-pretomanid-linezolid.
Notably, bedaquiline-pretomanid-JSF-3285 showed sterilizing efficacy comparable to bedaquiline-pretomanid-linezolid. This finding is highly impactful, as it suggests that a KasA inhibitor like JSF-3285 could provide an effective alternative to bedaquiline- pretomanid-linezolid, potentially bypassing the problem of linezolid toxicity.
The addition of moxifloxacin to bedaquiline-pretomanid-JSF-3285 further increased efficacy, resulting in a four-drug regimen that was superior to bedaquiline-pretomanid-linezolid and had sterilizing activity nearly identical to bedaquiline-pretomanid-linezolid-JSF-3285. Bedaquiline-pretomanid-moxifloxicin-JSF-3285 was also significantly more active than bedaquiline-pretomanid-moxifloxicin or bedaquiline-pretomanid-JSF-3285 alone.
These results indicate that JSF-3285 could potentially replace linezolid or moxifloxacin in current bedaquiline-pretomanid-linezolid-moxifloxacin regimens, offering improved tolerability and overcoming fluoroquinolone resistance. It could also serve as an alternative to bedaquiline-pretomanid-moxifloxacin-pyrazinamide, which has been associated with hepatotoxicity.
While JSF-3285's contribution to bedaquiline-pretomanid-based regimens is clear, it's worth noting that it did not show additive activity with all combinations and, in some cases, exhibited antagonistic effects This highlights the complex nature of drug interactions and the need for careful regimen design.
Nevertheless, JSF-3285 stands out as a promising preclinical candidate for TB treatment. Its ability to potently inhibit KasA, its effectiveness against drug-resistant strains, and its significant additive and sterilizing activity when combined with bedaquiline and pretomanid position it as a potential game-changer for both drug-sensitive and drug-resistant TB infections. Further studies, including in animal models that develop caseating lung lesions (different from the models evaluated here), are warranted to fully confirm its potential to replace existing drugs in WHO-recommended regimens.
Soni H, Tyagi S, Mane K, Shelke AM, Kumar P, Kaya F, Alland D, Zimmerman M, Freundlich JS, Nuermberger EL. The KasA inhibitor JSF-3285 improves the sterilizing activity of bedaquiline-pretomanid-containing regimens in a mouse model of tuberculosis. Antimicrob Agents Chemother. 2025 Jun 4;69(6):e0013025. doi: 10.1128/aac.00130-25. Epub 2025 Apr 23. PMID: 40265947; PMCID: PMC12135538.
Comments