Mycobacterium leprae is naturally resistant to PA-824

Abstract

Leprosy responds very slowly to the current multidrug therapy, and hence there is a need for novel drugs with potent bactericidal activity. PA-824 is a 4-nitroimidazo-oxazine that is currently undergoing phase I clinical trials for the treatment of tuberculosis. The activity of PA-824 against Mycobacterium leprae was tested and compared with that of rifampin in axenic cultures, macrophages, and two different animal models. Our results conclusively demonstrate that PA-824 has no effect on the viability of M. leprae in all three models, consistent with the lack of the nitroimidazo-oxazine-specific nitroreductase, encoded by Rv3547 in the M. leprae genome, which is essential for activation of this molecule.

FIG. 1.

Effect of PA-824 on the viability of extracellular (A) and intracellular (B) M. leprae. Viability was measured by the radiorespirometry method (n = 4 replicates for each concentration). The bar graphs show the means ± standard deviations of cumulative radiorespirometry counts. cpm, counts per minute.

FIG. 2.

Effects of PA-824 and rifampin on the multiplication of M. leprae in BALB/c and nude mice. The drugs were given orally in a CM-2 formulation for 4 weeks during the third month. (A) Growth kinetics of M. leprae in BALB/c mice. The drug treatment and harvest time points are indicated by arrows. (B) AFB counts were measured at the plateau and 4 weeks later in all groups (n = 5) of BALB/c mice. Drugs were administered at 8, 100, and 25 mg/kg as indicated in the key. (C) AFB counts measured 6 months postinfection in the nude mouse model (n = 5). (D) Photographs of drug-treated nude mouse footpads before harvest. FP, footpad; RMP, rifampin; P, plateau in AFB growth; W, weeks.

FIG. 3.

A proposed pathway for activation of PA-824. M. leprae and M. tuberculosis genes involved in nitro-reductive activation of PA-824 are shown.