C25-modified rifamycin derivatives with improved activity against <i>Mycobacterium abscessus</i>

Abstract

Infections caused by <i>Mycobacterium abscessus</i> are difficult to treat due to its intrinsic resistance to most antibiotics. Formation of biofilms and the capacity of <i>M. abscessus</i> to 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 Arr_Mab, an ADP-ribosyltransferase conferring resistance to rifampicin (RMP). Unlike RMP, 5j, a benzyl piperidine rifamycin derivative with a morpholino substituted C3 position and a naphthoquinone core, is not modified by purified Arr_Mab. Additionally, we show that the Arr_Mab D82 residue is essential for catalytic activity. Thermal profiling of Arr_Mab in the presence of 5j, RMP, or rifabutin shows that 5j does not bind to Arr_Mab. We found that the activity of 5j is comparable to amikacin against <i>M. abscessus</i> planktonic cultures and pellicles. Critically, 5j also exerts potent antimicrobial activity against <i>M. abscessus</i> in human macrophages and shows synergistic activity with amikacin and azithromycin.