Assessment of Clofazimine and TB47 Combination Activity against Mycobacterium abscessus Using a Bioluminescent Approach

Abstract

<i>Mycobacterium abscessus</i> is intrinsically resistant to most antimicrobial agents. The emerging infections caused by <i>M. abscessus</i> and the lack of effective treatment call for rapid attention. Here, we intended to construct a selectable marker-free autoluminescent <i>M. abscessus</i> strain (designated UAlMab) as a real-time reporter strain to facilitate the discovery of effective drugs and regimens for treating <i>M. abscessus</i> The UAlMab strain was constructed using the <i>dif</i>/Xer recombinase system. <i>In vitro</i> and <i>in vivo</i> activities of several drugs, including clofazimine and TB47, a recently reported cytochrome <i>bc</i>₁ inhibitor, were assessed using UAlMab. Furthermore, the efficacy of multiple drug combinations, including the clofazimine and TB47 combination, were tested against 20 clinical <i>M. abscessus</i> isolates. The UAlMab strain enabled us to evaluate drug efficacy both <i>in vitro</i> and in live BALB/c mice in a real-time, noninvasive fashion. Importantly, although TB47 showed marginal activity either alone or in combination with clarithromycin, amikacin, or roxithromycin, the drug markedly potentiated the activity of clofazimine, both <i>in vitro</i> and <i>in vivo</i> This study demonstrates that the use of the UAlMab strain can significantly facilitate rapid evaluation of new drugs and regimens. The clofazimine and TB47 combination is effective against <i>M. abscessus</i>, and dual/triple electron transport chain (ETC) targeting can be an effective therapeutic approach for treating mycobacterial infections.