C25-modified rifamycin derivatives with improved activity against Mycobacterium abscessus

Infections caused by Mycobacterium abscessus are difficult to treat due to its intrinsic resistance to most antibiotics. Formation of biofilms and the capacity of M. abscessus 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 M. abscessus planktonic cultures and pellicles. Critically, 5j also exerts potent antimicrobial activity against M. abscessus in human macrophages and shows synergistic activity with amikacin and azithromycin.

Automated summary

This study explored the modification of rifamycin SV to block enzymatic inactivation by Arr(Mab), a gene conferring resistance to rifampicin in Mycobacterium abscessus infections. A new rifamycin derivative called 5j showed comparable antimicrobial activity to amikacin and exhibited synergistic effects with amikacin and azithromycin in eradicating M. abscessus in human macrophages.