Statin adjunctive therapy shortens the duration of TB treatment in mice

Background: The repurposing of existing agents may accelerate TB drug development. Recently, we reported that the Lipid-Lowering drug simvastatin, when added to the first-Line antitubercular regimen, reduces the Lung bacillary burden in chronically infected mice. Objectives: We investigated whether the addition of simvastatin to the first-Line regimen (isoniazid/rifampicin/ pyrazinamide) shortens the duration of curative TB treatment in mice. Methods: Mycobacterium tuberculosis-infected THP-1 cells were exposed to simvastatin to determine the effect of statins on the activity of first-Line anti-TB drug activity and intracellular rifampicin concentration. Single-dose and steady-state pharmacokinetic studies guided optimized simvastatin dosing in vivo. BALB/c mice were aerosol -infected with M. tuberculosis H37Rv and drug treatment was initiated 6 weeks post-infection. Separate groups of mice received standard TB treatment with or without simvastatin. Relapse rates were assessed 3 months after discontinuation of each treatment regimen. MALDI-MS imaging was used to image the cholesterol content of mouse Lung Lesions. Results: Simvastatin significantly enhanced the bactericidal activity of first-Line drugs against intracellular M. tuberculosis without altering intracellular rifampicin concentrations. Adjunctive treatment with 60 mg/kg simvastatin shortened the time required to achieve culture-negative Lungs from 4.5 to 3.5 months. Following 2.5, 3.5 and 4.5 months of treatment, relapse rates were 100%, 50% and 0%, respectively, in the control group and 50% (P=0.03), 20% and 0%, respectively, in the statin group. Simvastatin did not alter plasma or Lung Lesion cholesterol Levels. Conclusions: Statins are attractive candidates for host-directed, adjunctive TB therapy. Further preclinical studies are needed to define the optimal statin and dosing.