A Novel Thiopeptide Exhibits In Vitro and In Vivo Synergistic Antibacterial Activity with Macrolide Against Mycobacterium avium Complex Infection.

The limitations of the current standard therapy for pulmonary diseases caused by Mycobacterium avium complex (MAC) underscore the urgent need for novel therapeutic agents. Among potential candidates, thiopeptide antibiotics have attracted attention due to their antibacterial activity but their poor solubility has limited clinical application. In this study, we developed AJ-099, a thiopeptide derivative with improved solubility and enhanced antibacterial potency. The in vitro antibacterial activity of AJ-099 was confirmed across macrolide-susceptible and- resistant clinical isolates, with minimum inhibitory concentration values consistently falling within the range of ≤0.125-0.5 μg/mL. In addition, AJ-099 exhibited a marked growth inhibition against both macrolide-susceptible and -resistant MAC clinical isolates in macrophages. Importantly, AJ-099 displayed synergistic effects in combination with clarithromycin (CLR), a macrolide drug, which resulted in significantly greater reductions in intracellular MAC burden compared to either agent alone. The synergistic effect was consistently observed in vivo, where the AJ-099 and CLR combination achieved superior bacterial clearance and reduced lung inflammation to the current standard therapy consisting of CLR, ethambutol, and rifampicin. Collectively, these results highlight that AJ-099 in combination with macrolides is a promising candidate for treating MAC pulmonary infections. Moreover, its potent activity against macrolide-resistant MAC strains suggests it may offer an effective therapeutic option for refractory MAC pulmonary infections.