GSK2556286 Is a Novel Antitubercular Drug Candidate Effective In Vivo with the Potential To Shorten Tuberculosis Treatment

Abstract

As a result of a high-throughput compound screening campaign using Mycobacterium tuberculosis-infected macrophages, a new drug candidate for the treatment of tuberculosis has been identified. GSK2556286 inhibits growth within human macrophages (50% inhibitory concentration [IC50] = 0.07 μM), is active against extracellular bacteria in cholesterol-containing culture medium, and exhibits no cross-resistance with known antitubercular drugs. In addition, it has shown efficacy in different mouse models of tuberculosis (TB) and has an adequate safety profile in two preclinical species. These features indicate a compound with a novel mode of action, although still not fully defined, that is effective against both multidrug-resistant (MDR) or extensively drug-resistant (XDR) and drug-sensitive (DS) M. tuberculosis with the potential to shorten the duration of treatment in novel combination drug regimens. (This study has been registered at ClinicalTrials.gov under identifier NCT04472897).

Keywords: GSK2556286; Mycobacterium tuberculosis; mouse; pharmacology; relapse; tuberculosis.

Conflict of interest statement

The authors declare a conflict of interest. Maria Santos Martínez-Martínez, Jorge Esquivias, Juan Miguel Siles, Marta Alonso, Jaime Escribano, Joaquin Rullas-Trincado, Esther Pérez-Herrán, Gareth Maher-Edwards, Joel Lelievre, Elena Jimenez, Olalla Sanz, Gary Boyle, Sam Turner, Beatriz Urones, Robert H. Bates, David Barros, are employees of GlaxoSmithKline. Eric L. Nuermberger receives research support from Janssen and the TB Alliance.

Figures

FIG 1

Chemical structure of GSK2556286.

FIG 2

Synthetic route to GSK2556286 (GSK3). TBME, tert-butyl methyl ether.

FIG 3

Lung CFU counts after 8 days of GSK2556286 treatment in an acute infection model in C57BL/6 mice. Data points represent individual mouse results. Open triangles represent mice from an initial experiment with a higher dose range. Solid circles represent mice from a second experiment with a lower, but overlapping, dose range. Solid lines represent fitted sigmoidal dose-response (A) and whole-blood exposure-response (B) curves, where AUClast is the AUC0–24. Horizontal dotted lines show thresholds for a 2-log10 reduction in CFU compared to untreated mice and the lower limit of CFU detection, as indicated.

FIG 4

Lung CFU counts after 4 weeks of GSK2556286 treatment in chronic infection models in BALB/c and C3HeB/FeJ mice. Data points represent individual mouse results. Horizontal bars represent the mean and median values for BALB/c and C3HeB/FeJ mice, respectively. D0, day 0; INH, isoniazid; GSK’286, GSK2556286.

FIG 5

Efficacy of GSK2556286 (G) combined with the various 2- and 3-drug combinations of B (bedaquiline), Pa (pretomanid), and L (linezolid) for 1 month (A) or 2 months (B) in a C3HeB/FeJ mouse model of TB. For comparison, B, BG, and BPaL are included. Bars indicate median CFU counts. The median CFU on day 0, the start of treatment, is indicated by the dotted line.