C25-modified rifamycin derivatives with improved activity against Mycobacterium abscessus
Laura Paulowski, Katherine S H Beckham, Matt D Johansen, Laura Berneking, Nhi Van, Yonatan Degefu, Sonja Staack, Flor Vasquez Sotomayor, Lucia Asar, Holger Rohde, Bree B Aldridge, Martin Aepfelbacher, Annabel Parret, Matthias Wilmanns, Laurent Kremer, Keith Combrink, Florian P Maurer
PNAS Nexus, Volume 1, Issue 4, September 2022, pgac130, https://doi.org/10.1093/pnasnexus/pgac130
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 (RMP). Unlike RMP, 5j, a benzyl piperidine rifamycin derivative with a morpholino substituted C3 position and a naphthoquinone core, 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, RMP, or rifabutin shows that 5j does not bind to ArrMab. We found that the activity of 5j is comparable to amikacin against M. abscessusplanktonic cultures and pellicles. Critically, 5j also exerts potent antimicrobial activity against M. abscessus in human macrophages and shows synergistic activity with amikacin and azithromycin.