Repositioning rifamycins for Mycobacterium abscessus lung disease

Abstract

Introduction: The treatment of Mycobacterium abscessus lung disease faces significant challenges due to intrinsic antibiotic resistance. New drugs are needed to cure this incurable disease. The key anti-tubercular rifamycin, rifampicin, suffers from low potency against M. abscessus and is not used clinically. Recently, another member of the rifamycin class, rifabutin, was shown to be active against the opportunistic pathogen. Areas covered: In this review, the authors discuss the rifamycins as a reemerging drug class for treating M. abscessus infections. The authors focus on the differential potency of rifampicin and rifabutin against M. abscessus in the context of intrinsic antibiotic resistance and bacterial uptake and metabolism. Reports of rifamycin-based drug synergies and rifamycin potentiation by host-directed therapy are evaluated. Expert opinion: While repurposing rifabutin for M. abscessus lung disease may provide some immediate relief, the repositioning (chemical optimization) of rifamycins offers long-term potential for improving clinical outcomes. Repositioning will require a multifaceted approach involving renewed screening of rifamycin libraries, medicinal chemistry to improve 'bacterial cell pharmacokinetics', better models of bacterial pathophysiology and infection, and harnessing of drug synergies and host-directed therapy towards the development of a better drug regimen.

Keywords: Lung disease; Mycobacterium abscessus; non-tuberculous mycobacteria; repositioning; rifamycins.

Figure 1.. Impact of known and potential M. abscessus intrinsic antibiotic resistance mechanisms on rifamycin bacterial cell pharmacokinetics.

Rifabutin (gold circles) accumulates to higher levels in M. abscessus than rifampicin (purple circles) (our unpublished data). Therefore, rifabutin and rifampicin demonstrate differential bacterial cell pharmacokinetics due to differences in metabolism, uptake or efflux. The low permeability of the M. abscessus outer membrane restricts the uptake of rifamycins which cross this barrier by passive diffusion. Because rifampicin contains a hydroquinone (highlighted red in structure), this compound is prone to autoxidation, which may occur inside or outside of the cell. Rifampicin’s hydroquinone would also be susceptible to inactivation by a Rox monooxygenase (Rox_Mab, potential resistance mechanism, dashed line). In contrast, rifabutin does not have a hydroquinone and would resist autoxidation or inactivation by Rox_Mab. The ADP-ribosyltransferase Arr_Mab catalyzes ADP-ribosylation at the C23 hydroxyl group of both rifamipicin and rifabutin (highlighted blue in structures). Rifamycins are removed from the cell by the putative efflux pump MAB_1409c (homolog of M. tuberculosis Rv1258c).