Omadacycline Potentiates Clarithromycin Activity Against Mycobacterium abscessus

Abstract

<i>Mycobacterium abscessus</i> is a difficult respiratory pathogen to treat, when compared to other nontuberculus mycobacteria (NTM), due to its drug resistance. In this study, we aimed to find a new clarithromycin partner that potentiated strong, positive, synergy against <i>M. abscessus</i> among current anti-<i>M. abscessus</i> drugs, including omadacycline, amikacin, rifabutin, bedaquiline, and cefoxitine. First, we determined the minimum inhibitory concentrations required of all the drugs tested for <i>M. abscessus</i> subsp. <i>abscessus</i> CIP104536^T treatment using a resazurin microplate assay. Next, the best synergistic partner for clarithromycin against <i>M. abscessus</i> was determined using an <i>in vitro</i> checkerboard combination assay. Among the drug combinations evaluated, omadacycline showed the best synergistic effect with clarithromycin, with a fractional inhibitory concentration index of 0.4. This positive effect was also observed against <i>M. abscessus</i> clinical isolates and anti-<i>M. abscessus</i> drug resistant strains. Lastly, this combination was further validated using a <i>M. abscessus</i> infected zebrafish model. In this model, the clarithromycin-omadacyline regimen was found to inhibit the dissemination of <i>M. abscessus,</i> and it significantly extended the lifespan of the <i>M. abscessus</i> infected zebrafish. In summation, the synergy between two anti-<i>M. abscessus</i> compounds, clarithromycin and omadacycline, provides an attractive foundation for a new <i>M. abscessus</i> treatment regimen.