Mycobacterium abscessus is a multidrug-resistant fast-growing nontuberculous mycobacteria (NTM) that is a growing public health threat among patients with weakened immune systems or preexisting pulmonary diseases. Current treatment regimens of M. abscessus infections, employing an oral macrolide (typically clarithromycin) in combination with limited injectable antibiotics, only result in modest clinical cure rates due to the intrinsic resistance of M. abscessus to virtually every class of existing antibiotics, which poses serious challenges to the development of effective therapeutics. Although rifamycins are one of the most powerful and effective classes of antimicrobials for treating many mycobacterial infections—because of their potent sterilizing activity against the heterogenous mycobacterial populations and superb lesion penetration—they are 50 and up to 500-fold less active against M. abscessus. The poor susceptibility of M. abscessus is caused by a novel drug inactivation mechanism performed by a mycobacterial ADP-ribosyltransferase (Arr), which catalyzes ADP-ribosylation of the 23-hydroxyl group of rifamycins (Figure 1A). Aiming at developing chemotherapeutics against M. abscessus with significantly improved efficacy, we modified the rifamycin drug rifabutin using a structure-based drug design approach. The C25-oxygen of rifabutin was specifically derivatized, through a carefully designed synthetic route, to prevent Arr-mediated ADP-ribosylation while maintaining favorable binding to the therapeutic target-RNA polymerase β subunit (RPoB) (Figure 1B). Several 25-O-modified rifabutin derivatives were identified that restored low nanomolar activity against M. abscessus and completely overcame the Arr-mediated resistance (Figure 1C), which was further supported by structural characterization and in vitro HPLC-based Arr-biochemical assays. The selected leads were further demonstrated to maintain exceptional activity against M. abscessus clinical isolates and possess outstanding in vivo pharmacokinetic properties (Figure 1C).

Rationally designed rifabutin analogs overcoming intrinsic drug resistance are highly effective against Mycobacterium abscessus

ACS Spring 2022

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.