Contribution of direct InhA inhibitors to novel drug regimens in a mouse model of tuberculosis

Abstract

Isoniazid is an important first-line medicine to treat tuberculosis (TB). Isoniazid resistance increases the risk of poor treatment outcomes and development of multidrug resistance, and is driven primarily by mutations involving katG, encoding the prodrug-activating enzyme, rather than its validated target, InhA. The chemical tractability of InhA has fostered efforts to discover direct inhibitors of InhA (DIIs). In this study, we bridge the gap in understanding the potential contribution of DIIs to novel combination regimens and demonstrate a clear distinction of DIIs, like GSK693 and the newly described GSK138, from isoniazid, based on activity against clinical isolates and contribution to novel drug regimens. The results suggest that DIIs, specifically GSK138 and GSK693, could be promising partners in novel drug regimens, including those used against isoniazid-resistant TB, potentially enhancing their efficacy and/or preventing the selection of resistant mutants and supporting the continued exploration of InhA as a promising target for TB drug development.

Keywords: GSK138; GSK2505693A; GSK3081138A; GSK693; InhA inhibitor; mouse; tuberculosis; tuberculosis drugs.

Fig 1

Dose-response relationship for GSK138 in an acute mouse infection model of TB. Each point represents data from an individual mouse that received GSK138 administered orally once daily for 8 days.

Fig 2

Mean (±SD) lung CFU counts at D0 and after 4 (A) or 8 (B) weeks of treatment in experiment 1. In combination with RZ, but not with other drugs, GSK693 showed significantly enhanced antibacterial activity at week 8 (B) but not at week 4 (A). Open bars show lung CFU counts with the addition of GSK693 to drugs, shown in solid bars. Drug doses: R, 10 mg/kg; Z, 150 mg/kg; H, 10 mg/kg; 693, 300 mg/kg; Pa, 50 mg/kg; M, 100 mg/kg; B, 25 mg/kg; L, 100 mg/kg; and U, 50 mg/kg. 693, GSK693; B, bedaquiline; H; isoniazid; L, linezolid; M, moxifloxacin; Pa, pretomanid; R, rifampicin; RZ, rifampicin and pyrazinamide; U, sutezolid; Z, pyrazinamide

Fig 3

Mean (±SD) lung CFU counts at D0 and after 8 weeks of treatment in experiment 2. GSK693 significantly enhanced, in a non-dose-dependent manner, the activity of the RZ (rifampicin, 10 mg/kg, plus pyrazinamide 150 mg/kg) combination. Isoniazid (10 mg/kg) did not enhance the activity of the combination. GSK693 dose (in mg/kg) is indicated in subscripts. 693, GSK693.

Fig 4

The direct InhA inhibitor GSK138 enhanced the activity of the BPa, BPaL, and BPa + GSK656 combinations after 4 weeks (A) or 8 weeks (B) of treatment in experiment 3. After 8 weeks of treatment, the BPaL + GSK138 regimen rendered mouse lung cultures negative. Data are presented as mean (±SD) lung CFU counts. R, 10 mg/kg; Z, 150 mg/kg, H, 10 mg/kg; 138, 200 mg/kg; 656 (sulfate salt), 10 mg/kg; Pa, 50 mg/kg; B, 25 mg/kg; L, 100 mg/kg. 138 = GSK138; 656, GSK656; B, bedaquiline; H, isoniazid; L, linezolid; NT, not tested; Pa, pretomanid; R, rifampicin; Z, pyrazinamide.

Fig 5

GSK138 significantly enhanced the activity of BPa and BPa-based regimens at 4 weeks (A) or 8 weeks (B), particularly in combination with GSK286. In combination with GSK656 or GSK286, the 200-mg/kg dose of GSK138 was used. Data are presented as mean (±SD) lung CFU counts. B, 25 mg/kg; Pa, 100 mg/kg; L, 100 mg/kg; H, 10 mg/kg; 286, 50 mg/kg; 656 (hydrochloride salt), 10 mg/kg. GSK138 dose (in mg/kg) is indicated in subscripts. 286, GSK286; 656, GSK656; B, bedaquiline; H, isoniazid; L, linezolid; Pa, pretomanid.

Fig 6

The addition of an InhA inhibitor or moxifloxacin enhanced the bactericidal and sterilizing activity of the BPaL regimen. After both 4 weeks (A) and 8 weeks (B), the addition of moxifloxacin, isoniazid, NITD-113, or GSK138 to BPaL enhanced the bactericidal activity compared to BPaL alone (with the exception of isoniazid at week 8). Data are presented as mean (±SD) lung CFU counts. The proportion of mice relapsing after 8 weeks of treatment, followed by 12 weeks of no treatment (C), was statistically significantly lower in the presence of either moxifloxacin or isoniazid and approached statistical significance with GSK138. There were fewer relapses after 12 weeks of treatment and 12 weeks of follow-up (D) with the addition of a fourth drug, although these differences were not statistically significant. The proportions of mice relapsing are indicated above the symbols for lung CFU counts. B, 25 mg/kg; Pa, 100 mg/kg; L, 100 mg/kg; M, 100 mg/kg; H, 10 mg/kg; NITD-113 (see Introduction), 150 mg/kg; 138, 200 mg/kg. 138, GSK138; B, bedaquiline; H, isoniazid; L, linezolid; M, moxifloxacin; NITD-113, prodrug for NITD-916; NT, not tested; Pa, pretomanid.