Epetraborole Is Active against Mycobacterium abscessus

Abstract

Benzoxaboroles are a new class of leucyl-tRNA synthetase inhibitors. We recently reported that the antitubercular 4-halogenated benzoxaboroles are active against Mycobacterium abscessus . Here, we find that the non-halogenated benzoxaborole epetraborole, a clinical candidate developed for Gram negative infections, is also active against M. abscessus in vitro and in a mouse model of infection. This expands the repertoire of advanced lead compounds for the discovery of a benzoxaborole-based candidate to treat M. abscessus lung disease.

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.…”

A Novel Leucyl-tRNA Synthetase Inhibitor, MRX-6038, Expresses Anti-Mycobacterium abscessus Activity In Vitro and In Vivo

“…Sequencing leuS suggested that all resistant isolates had a single missense mutation in the leuS editing domain (residues 292 to 502), consistent with the mechanism of leucyl-tRNA synthetase inhibition. The S303L, V417M, and T322I residues were mutated in benzoxaborole-resistant M. abscessus mutants that were previously reported ( 18 , 19 ). Four other LeuRS missense mutations in the editing domain (i.e., D436E, L418P, Y421H, and D436N) were novel.…”

Activity of Tricyclic Pyrrolopyrimidine Gyrase B Inhibitor against Mycobacterium abscessus

“…Despite M. abscessus resistance to most approved anti-TB drugs, we found that compound collections of TB actives provide a good source for hit identification (6). Screening series of advanced TB actives against M. abscessus identified several compounds with in vivo activity, including inhibitors of RNA polymerase (7), ATP synthase (8), Leucyl-tRNA synthetase (9, 10), DNA gyrase (11) and DNA clamp DnaN (12). Expanding on this strategy, we asked whether the recently identified novel class of tricyclic pyrrolopyrimidines (TPPs (13)), targeting DNA gyrase in Mycobacterium tuberculosis and various other bacteria (14, 15) is active against M. abscessus .…”

“…synthetase (9,10), DNA gyrase (11) and DNA clamp DnaN (12). Expanding on this strategy, we asked whether the recently identified novel class of tricyclic pyrrolopyrimidines (TPPs (13)), targeting DNA gyrase in Mycobacterium tuberculosis and various other bacteria (14,15) is active against M. abscessus.…”