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

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.

Efficacy of epetraborole against Mycobacterium abscessus is increased with norvaline

“…Our data and two recent publications [43,44] confirmed the activity of benzoxaboroles against mycobacteria using zebrafish and murine models of infection and we showed that benzoxaboroles can be potentiated when combined with norvaline. Specifically, we demonstrated that the combination of EPT with norvaline reduces the emergence of M. abscessus and M. tuberculosis mutants and results in increased activity in vivo compared to EPT.…”

Epetraborole Is Active against Mycobacterium abscessus

“…In conclusion, we show that epetraborole, an advanced nonhalogenated 3-aminomethyl benzoxaborole developed for Gram-negative infections, is also active against M. abscessus in vitro and in a mouse model of infection. This agrees with a recent publication that identified epetraborole in a screen of the MMV pandemic response box for anti- M. abscessus activity and reported this compound’s efficacy against M. abscessus in a zebrafish infection model ( 19 ). Our findings reaffirm leucyl-tRNA synthetase as an attractive target against M. abscessus and expand the repertoire of advanced lead compounds for the discovery of a benzoxaborole-based candidate for the treatment of M. abscessus lung disease.…”

Screening of the Pandemic Response Box Reveals an Association between Antifungal Effects of MMV1593537 and the Cell Wall of Cryptococcus neoformans , Cryptococcus deuterogattii , and Candida auris

“…The box corresponds to a collection of 400 structurally diverse compounds for screening against infectious diseases and other neglected maladies. Within this compound collection, inhibitors of the replication of SARS Cov 2 ( 14 ) and Zika virus ( 15 ), in addition to anti-amoebic drugs ( 16 ), antimalarials ( 17 ), antischistosomals ( 18 ), and inhibitors of Mycobacterium abscessus ( 19 ) have been described. In this study, we screened the Pandemic Response Box collection for activity against three fungal pathogens with high lethality and exceedingly ineffective treatment options: Cryptococcus neoformans , Cryptococcus deuterogattii , and C. auris .…”