Old antibiotics pair to beat drug-resistant TB and related infections

Antimicrobial resistance is a growing global threat that makes familiar infections harder to treat. In particular, Mycobacterium tuberculosis and a group called non-tuberculous mycobacteria, including M. abscessus, are increasingly showing resistance to the drugs clinicians rely on. Faced with this challenge, researchers led by Arunava Dasgupta looked for new ways to use existing drugs more effectively. Rather than seeking entirely new molecules, they tested combinations of antibiotics to see whether pairs might kill resistant bacteria more potently and reduce the chance that resistance would emerge. In their work they focused on Vancomycin, a glycopeptide long used for other bacterial infections, alongside a broad class of drugs called β-lactams. The team screened multiple β-lactams to find partners that, when paired with Vancomycin, could overcome the defenses of drug-resistant mycobacterial strains. Their goal was to identify combinations that not only stopped growth in the lab but also reduced bacterial load in infected animals, offering a potential path to treat stubborn infections caused by drug-resistant mycobacteria.

The study identified combinations of Vancomycin with several β-lactams as having potent activity against drug-resistant Mycobacterium tuberculosis and non-tuberculous mycobacteria including M. abscessus. In particular, Ceftriaxone, Ceftazidime and Meropenem, tested with or without Sulbactam, a β-lactamase inhibitor, showed strong effects. The Vancomycin and β-lactam pairs demonstrated bactericidal activity in vitro and reduced bacterial counts better than either drug alone. To explore how the drugs worked together, the researchers used an ethidium bromide assay and found evidence that the combination increases permeability of the mycobacterial cell, which provides a molecular basis for the observed synergy. The team also tested the combinations in a murine model of mycobacterial infection. There, the Vancomycin plus β-lactam regimens outperformed clinically utilized drugs including Isoniazid, Rifampicin and Ethambutol against M. tuberculosis, and outperformed Amikacin and Clarithromycin against M. abscessus, producing significant reductions in bacterial load across multiple organs.

These results point to a practical strategy for dealing with recalcitrant mycobacterial infections caused by drug-resistant strains. By combining Vancomycin with selected β-lactams such as Ceftriaxone, Ceftazidime and Meropenem, and by using Sulbactam where helpful, the researchers demonstrated both stronger killing in the lab and better clearance in animals than standard therapies. The finding that increased cell permeability underlies the synergy suggests a clear mechanism that can guide further optimization of combinations. Importantly, the combinations worked against diverse resistant strains, raising the possibility that they could be repurposed for hard-to-treat cases. While the work reported here is preclinical, it supports further study of Vancomycin plus β-lactam combinations as potential treatment options and as a way to slow the emergence of new resistance among mycobacterial pathogens.