Multipronged Cell Wall-Targeting Converts Ineffective Antibiotics into a Potent Regimen against Mycobacterium...

Mycobacterium abscessus is an intrinsically drug-resistant pathogen responsible for chronic lung infections that are notoriously difficult to cure. Its complex, multilayered cell wall limits drug penetration and underlies the poor efficacy of most antibiotics. Here, we show that targeting multiple components of cell wall biosynthesis simultaneously can convert otherwise inactive agents into potent, bactericidal combinations. Pairing glycopeptides with β-lactams led to synergistic killing, while inclusion of ethambutol further enhances potency. Mechanistic studies indicated that the combinations act through cumulative weakening of the cell envelope. Concomitant inhibition of peptidoglycan and arabinogalactan or lipoarabinomannan synthesis caused extensive ATP leakage and improved access of vancomycin to its targets, consistent with additive structural damage. This multilayered disruption rendered the cell wall unable to maintain integrity. The triple combination of teicoplanin, cefoxitin and ethambutol also decreased lung bacterial loads in mice infected with M. abscessus. These findings establish that intrinsic antibiotic resistance in M. abscessus can be overcome by coordinated interference with cell wall biogenesis using clinically available antibiotics. This strategy provides a mechanistic framework for rational repurposing of existing drugs to treat nontuberculous mycobacterial infections for which new therapies are urgently needed.