C25-modified rifamycin derivatives with improved activity againstMycobacterium abscessus

Abstract

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 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 ArrMab D82 residue is essential for catalytic activity. Thermal profiling of ArrMab in 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 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.

Novel synergies and isolate specificities in the drug interactions landscape ofMycobacterium abscessus

“…Though rifabutin, another rifamycin antibiotic, has been approved to treat Mycobacterium Avium Complex and TB, its potential against M. abscessus has not been fully explored. Recent findings demonstrate limited modification of rifabutin by the Arr Mab in comparison to rifampicin, resulting in lower MICs against both the ATCC19977 strain and clinical M. abscessus isolates (42). We also observed in our dataset that rifabutin has a lower IC 50 and is more potent than rifampicin (IC 50 of 1.8μg/mL versus 16 μg/mL, respectively, Table 1, Fig.…”