Rifaximin potentiates clarithromycin against Mycobacterium abscessus in vitro and in zebrafish

BACKGROUND: Mycobacterium abscessus is a non-tuberculous mycobacterium (NTM) that causes chronic pulmonary infections. Because of its extensive innate resistance to numerous antibiotics, treatment options are limited, often resulting in poor clinical outcomes. Current treatment regimens usually involve a combination of antibiotics, with clarithromycin being the cornerstone of NTM treatments. OBJECTIVES: To identify drug candidates that exhibit synergistic activity with clarithromycin against M. abscessus. METHODS: We performed cell-based phenotypic screening of a compound library against M. abscessus induced to become resistant to clarithromycin. Furthermore, we evaluated the toxicity and efficacy of the top compound in a zebrafish embryo infection model. RESULTS: The screen revealed rifaximin as a clarithromycin potentiator. The combination of rifaximin and clarithromycin was synergistic and bactericidal in vitro and potent in the zebrafish model. CONCLUSIONS: The data indicate that the rifaximin/clarithromycin combination is promising to effectively treat pulmonary NTM infections.