HMG-CoA Reductase Inhibitors

TB remains one of the leading causes of deaths by infectious diseases worldwide. The need to develop new, improved treatments remains urgent, and the repurposing of existing drugs represents a possible shortcut to market. Recently, there has been significant interest in host-directed adjuvant therapy to enhance bacillary killing. HMG-CoA reductase inhibitors (statins), which are among the most commonly prescribed drugs, have immunomodulatory properties and improve clinical outcomes of bacterial infections. We have studied the tuberculocidal activity of simvastatin alone and in combination with first-line anti-TB drugs in macrophages and in a murine model of chronic TB infection. Exposure to simvastatin 10μM significantly increased the tuberculocidal activity of isoniazid in J774 macrophages at Day 3 after infection versus isoniazid alone (p=0.02). Similarly, relative to the standard oral regimen of rifampin (10 mg/kg), isoniazid (10 mg/kg), and pyrazinamide (150 mg/kg) given 5 times weekly, the addition of simvastatin 25mg/kg enhanced bacillary killing, reducing lung CFU by an additional 1 log10 at Day 28 (p<0.01), and by a further 1.25 log10 at Day 56 (p<0.01). The potential additive activity of simvastatin to first-line TB treatment holds promise. However, further studies to identify the optimal statin and dosing are required. In addition, the ability of combination treatment with statins to accelerate the time required to achieve a stable cure remains to be explored.