Isolation of resistant mutants to epetraborole compound in Mycobacteroides abscessus

We identified epetraborole (EPT) from the Medicines for Malaria Venture (MMV) Open pandemic response box as a LeuRS inhibitor in M. abscessus with nanomolar activity in vitro. Interestingly, we note that EPT is more active against M. abscessus than M. tuberculosis and this discrepancy is not explained by differences in binding affinity to LeuRS as the editing domains are conserved across mycobacteria. Knowing that acquired resistance to EPT in M. tb results from mutations in critical residues in the editing domain, we pursued a means to limit this resistance.