The KasA inhibitor JSF-3285 improves the sterilizing activity of bedaquiline-pretomanid-containing regimens in a mouse model of tuberculosis

Abstract

JSF-3285 is a promising preclinical candidate for tuberculosis that potently targets the Mycobacterium tuberculosis β-ketoacyl-ACP synthase KasA. In mouse models of acute, sub-acute, chronic, and relapse infection, JSF-3285 offers substantial activity in combination with bedaquiline and pretomanid, which could be applicable for both drug-sensitive and drug-resistant infections.

Keywords: JSF-3285; KasA; Mycobacterium tuberculosis; antitubercular; mouse relapse model.

Fig 1

Mean (± SD) lung CFU counts after 1 month of treatment with increasing doses of JSF-3285 in the subacute mouse infection model. None, untreated (negative control). H, isoniazid 10 mg/kg (positive control). Points indicate CFU counts for individual mice. The dashed horizontal line indicates mean CFU count at Day 0.

Fig 2

Mean (± SD) lung CFU counts after 3 weeks of treatment in Experiment 2a evaluating the dose fractionation of JSF-3285 in monotherapy (A); and in Experiment 2b evaluating the dose-ranging activity of JSF-3285 in combination with bedaquiline (25 mg/kg) and pretomanid (50 mg/kg) (BPa) (B). None, untreated (negative control). H, isoniazid 10 mg/kg (positive control). Points indicate CFU counts for individual mice. Dashed horizontal lines indicate mean CFU count at Day 0. The lower limit of detection was 2.5 CFU, which translates to 0.54 log10 after adding 1 prior to log transformation. The treatment regimen indicated as 200 BID/QD was 200 mg/kg BID for 1 week and then 200 mg/kg QD for 2 weeks.

Fig 3

Dose–response relationships for JSF-3285 monotherapy in the subacute infection model in Experiment 1 (A) and the acute infection model in Experiment 2a (B). Dashed horizontal lines indicate the mean CFU count at Day 0. A dose of 0.01 mg/kg was substituted for 0 in untreated controls to enable log transformation and curve fitting.

Fig 4

Mean (± SD) lung CFU counts after 1 month (A) and 1.5 months (B) of treatment in Experiment 3. Red bars show data from groups receiving regimens containing PZ, blue bars show data from groups receiving regimens containing BPa but not Z, and green bars show data from groups receiving regimens containing BZ. K = JSF-3285 30 mg/kg, P = rifapentine 10 mg/kg, Z = pyrazinamide 150 mg/kg, H = isoniazid 10 mg/kg, M = moxifloxacin 100 mg/kg, B = bedaquiline 25 mg/kg, Pa = pretomanid 50 mg/kg, and L = linezolid 50 mg/kg. Points indicate CFU counts for individual mice. Dashed horizontal lines indicate mean CFU count at Day 0. The lower limit of detection was 2.5 CFU, which translates to 0.54 log10 after adding 1 prior to log transformation.

Fig 5

Mean (± SD) lung CFU after 1 month (A) and 2 months (B) of treatment in Experiment 5. Gray bars show data from the control regimens, BPaL and BPaMZ, open bars show data from test regimen backbones, and blue bars show data from groups receiving test regimen backbones plus JSF-3285. K = JSF-3285 30 mg/kg, P = rifapentine 10 mg/kg, Z = pyrazinamide 150 mg/kg, H = isoniazid 10 mg/kg, M = moxifloxacin 100 mg/kg, B = bedaquiline 25 mg/kg, Pa = pretomanid 50 mg/kg, L = linezolid (50 mg/kg), Rb = rifabutin (5 mg/kg), C = clofazimine (6.25 mg/kg), and A = TBA-7371 (200 mg/kg). Points indicate CFU counts for individual mice. Dashed horizontal lines indicate mean CFU count at Day 0. The lower limit of detection was 2.5 CFU, which translates to 0.54 log10 after adding 1 prior to log transformation.