Abstract
Mycobacterium abscessus is the one of the most feared bacterial respiratory pathogens in the world. Unfortunately, there are many problems with the current M. abscessus 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 M. abscessus, and these are present in preclinical and clinical development only. With that in mind, new and more powerful anti-M. abscessus medicines need to be discovered and developed. In this study, we conducted an in vitro-dual screen against M. abscessus rough (R) and smooth (S) variants using a Pandemic Response Box and identified epetraborole as a new effective candidate for M. abscessus therapy. For further validation, epetraborole showed significant activity against the growth of the M. abscessus wild-type strain, three subspecies, drug-resistant strains and clinical isolates in vitro, while also inhibiting the growth of M. abscessus 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-M. abscessus candidate in the M. abscessus drug search.
Highlights
IntroductionDespite great strides in the field of infectious disease over the past century, Mycobacterium abscessus (hereafter referred to as Mab) complex infection has remained a leading cause of morbidity and mortality in cystic fibrosis (CF) patients [1]
The library was obtained in plates from the Medicines for Malaria
ETB showed very close inhibitory concentration (IC) values when compared to wild-type Mab subsp. abscessus CIP104536T, to all AMK, CFX, and CLA resistant mutants. These results demonstrate that ETB is an active compound against wilt-type Mab, as well as against AMK, CFX, and CLA resistant strains
Summary
Despite great strides in the field of infectious disease over the past century, Mycobacterium abscessus (hereafter referred to as Mab) complex infection has remained a leading cause of morbidity and mortality in cystic fibrosis (CF) patients [1]. Mab infections are deadly complicated to treat due to their mechanisms for drug resistance and biofilm generation [2]. There is no compelling agent for Mab treatment: clarithromycin (CLA), amikacin (AMK), and cefoxitin (CFX) are currently used as a drug combination for 1 to 2 months, followed by an oral maintenance regimen, usually with a fluoroquinolone, based on the recommendations of experts [3]. Long-term and intensive combination therapy has shown high rates of treatment failure, recurrences, and adverse effects
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