Statins Increase Rifampin Mycobactericidal Effect

Abstract

Mycobacterium leprae and Mycobacterium tuberculosis antimicrobial resistance has been followed with great concern during the last years, while the need for new drugs able to control leprosy and tuberculosis, mainly due to extensively drug-resistant tuberculosis (XDR-TB), is pressing. Our group recently showed that M. leprae is able to induce lipid body biogenesis and cholesterol accumulation in macrophages and Schwann cells, facilitating its viability and replication. Considering these previous results, we investigated the efficacies of two statins on the intracellular viability of mycobacteria within the macrophage, as well as the effect of atorvastatin on M. leprae infections in BALB/c mice. We observed that intracellular mycobacteria viability decreased markedly after incubation with both statins, but atorvastatin showed the best inhibitory effect when combined with rifampin. Using Shepard's model, we observed with atorvastatin an efficacy in controlling M. leprae and inflammatory infiltrate in the BALB/c footpad, in a serum cholesterol level-dependent way. We conclude that statins contribute to macrophage-bactericidal activity against Mycobacterium bovis, M. leprae, and M. tuberculosis. It is likely that the association of statins with the actual multidrug therapy effectively reduces mycobacterial viability and tissue lesion in leprosy and tuberculosis patients, although epidemiological studies are still needed for confirmation.

Is There Potential for Repurposing Statins as Novel Antimicrobials?

“…The study further demonstrated that the simvastatinmediated decrease in bacterial growth was reversed by the presence of mevalonate, the product of HMG-CoA reductase, and suggested that statins control infection by phagolysosomal arrest of M. tuberculosis. These results were corroborated by those from a study by Lobato et al in which they showed that atorvastatin and simvastatin (2 M) significantly inhibited M. tuberculosis growth (circa 60% reduction) in macrophages and that this was again reversed by the presence of mevalonate (54). A previous study by Parihar et al also demonstrated that simvastatin treatment (20.6 mg/liter) could significantly reduce, by up to 4-fold (P Ͻ 0.001), the ability of the foodborne pathogen Listeria monocytogenes to grow inside mouse and primary macrophages, in a cholesteroldependent manner, and could significantly reduce bacterial burden and dissemination (by 100-fold) to the liver (P Ͻ 0.001) and spleen (P Ͻ 0.05) in infected mice (61).…”

“…A significant synergistic effect resulting in increased bacterial lysis has been reported with sublethal doses of penicillin and simvastatin (7.8 mg/liter) against pneumococcal growth in vitro (43), while atorvastatin and simvastatin (0.2 M) treatment increased the efficacy of rifampin against M. tuberculosis and M. leprae infection in vitro by approximately 50% (54). In addition, in vivo mouse studies showed that atorvastatin (80 mg/kg/day) treatment increased the efficacy of rifampin against M. leprae infection (P Ͻ 0.05) (54) and that simvastatin (25 mg/kg) treatment increased the in vivo activity of first-line anti-TB antibiotics, reducing the lung bacillary burden by Ͼ1 log 10 (P Ͻ 0.01) (82). Thangamani and colleagues demonstrated a positive synergistic effect of simvastatin on the antimicrobial effect of four topical antibiotics, mupirocin, fusidic acid, retapamulin, and daptomycin, against clinical isolates of multidrug-resistant S. aureus.…”

“…Several studies have shown that the observed effect of statin on bacterial virulence can be reversed by the addition of exogenous mevalonate (54, 59-61, 66, 69, 75, 77, 79), while statin-mediated cholesterol depletion is protective against bacterial toxins (61,75) and contributes to the killing of intracellular bacteria (45,54,(60)(61)(62)66). In addition, the regulation of the inflammatory response by statins may account for some of these protective effects.…”

“…Recent reports demonstrated that lovastatin at 0.4 mg/liter (53) and both atorvastatin and simvastatin, in a dose-dependent fashion (0.08 to 0.8 mg/ liter), reduced the survival of the leprosy-causing species Mycobacterium leprae (by up to 90% and 75%, respectively) in in vitro macrophage models, but in a cholesterol-dependent manner (54), suggesting an indirect effect on cholesterol levels, as the intracellular growth of these pathogens requires cholesterol. Prior but not concurrent treatment of murine fibroblast (L929) cells with lovastatin at 0.4 mg/liter also reduced both the intracellular growth of the respiratory pathogen Coxiella burnetii (which causes Q fever) (by 43%, P ϭ 0.064) (55) and plaque formation by the causative agent of Rocky mountain spotted fever, Rickettsia conorii (by 64%, P ϭ 0.003) (56).…”

Autophagy in the Fight Against Tuberculosis

“…In TB mice models, treatment with statins significantly reduced the bacterial load and the pulmonary pathological effects of TB infection (Parihar et al, 2014). It was further shown in TB-infected macrophages and in mice models that treatment with statins improves the efficacy of first-line TB drug regimens and of rifampicin alone (Lobato et al, 2014;Skerry et al, 2014). It was demonstrated that statins improve bacterial clearance by the host and improve the efficacy of TB drugs by promoting autophagy through inhibition of the HMG-CoA reductase pathway (Parihar et al, 2014).…”