A Screening of the MMV Pandemic Response Box Reveals Epetraborole as A New Potent Inhibitor against Mycobacterium abscessus

Abstract

<i>Mycobacterium abscessus</i> is the one of the most feared bacterial respiratory pathogens in the world. Unfortunately, there are many problems with the current <i>M. abscessus</i> therapies available. These problems include misdiagnoses, high drug resistance, poor long-term treatment outcomes, and high costs. Until now, there have only been a few new compounds or drug formulations which are active against <i>M. abscessus,</i> and these are present in preclinical and clinical development only. With that in mind, new and more powerful anti-<i>M. abscessus</i> medicines need to be discovered and developed. In this study, we conducted an in vitro-dual screen against <i>M. abscessus</i> rough (R) and smooth (S) variants using a Pandemic Response Box and identified epetraborole as a new effective candidate for <i>M. abscessus</i> therapy. For further validation, epetraborole showed significant activity against the growth of the <i>M. abscessus</i> wild-type strain, three subspecies, drug-resistant strains and clinical isolates in vitro, while also inhibiting the growth of <i>M. abscessus</i> that reside in macrophages without cytotoxicity. Furthermore, the in vivo efficacy of epetraborole in the zebrafish infection model was greater than that of tigecycline. Thus, we concluded that epetraborole is a potential anti-<i>M. abscessus</i> candidate in the <i>M. abscessus</i> drug search.