C25-modified rifamycin derivatives with improved activity againstMycobacterium abscessus

Infections caused byMycobacterium abscessusare difficult to treat due to its intrinsic resistance to most antibiotics. Formation of biofilms and the capacity ofM. abscessusto survive inside host phagocytes further complicate eradication. Herein, we explored whether addition of a carbamate-linked group at the C25 position of rifamycin SV blocks enzymatic inactivation by ArrMab, an ADP-ribosyltransferase conferring resistance to rifampicin. Unlike rifampicin, 5j, a benzyl piperidine rifamycin derivative with a morpholino substituted C3 position, is not modified by purified ArrMab. Additionally, we show that the ArrMabD82 residue is essential for catalytic activity. Thermal profiling of ArrMabin the presence of 5j, rifampicin or rifabutin shows that 5j does not bind to ArrMab. We found that the activity of 5j is comparable to amikacin againstM. abscessusplanktonic cultures and pellicles. Critically, 5j also exerts potent antimicrobial activity againstM. abscessusin human macrophages and shows synergistic activity with amikacin and azithromycin.