Lovastatin Has Significant Activity against Zygomycetes and Interacts Synergistically with Voriconazole

Abstract

Zygomycetes are emerging opportunistic molds resistant to most conventional antifungals. We evaluated the in vitro activity of lovastatin (LOV), a 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor, against seven clinical isolates of Zygomycetes by using standard microdilution methods in three different media, disk diffusion testing, and viability dye staining. To further study the in vivo efficacy of LOV against zygomycetes, we developed a Drosophila melanogaster model of zygomycosis. In different experiments, groups of Toll-deficient (Tl) flies fed LOV-containing food were subsequently injected with two representative Zygomycetes isolates (Mucor and Rhizopus spp.). Finally, we examined the effects of LOV on voriconazole (VRC) activity against zygomycetes in vitro by checkerboard dilution, Epsilometer test-based methods, and bis-(1,3-dibutylbarbituric acid) trimethine oxonol staining and in vivo in Tl flies fed food containing LOV plus VRC and infected with zygomycetes. LOV exhibited significant, medium, and strain-independent fungicidal activity against all Zygomycetes isolates in vitro by all testing methods (MIC 50 , 48.0 g/ml; 50% minimal fungicidal concentration, 56.0 g/ml; 50% effective concentration, 29.4 g/ml [6.6 to 38.9 g/ml]). Tl flies fed LOV-containing food and infected with Mucor had a significantly better 6-day survival rate than did infected Tl flies fed regular food (P ‫؍‬ 0.0005). LOV displayed in vitro synergy with VRC against all Zygomycetes isolates (fractional inhibitory concentration index, 0.104 to 0.290) by all methods used. LOV also displayed synergy with VRC in the Drosophila model of zygomycosis (P < 0.01). LOV is significantly active against zygomycetes and synergizes with triazoles inherently resistant to them, such as VRC. The clinical significance of these findings needs to be further explored.

Cloning of the Rhizomucor miehei 3-hydroxy-3-methylglutaryl-coenzyme A reductase gene and its heterologous expression in Mucor circinelloides

“…In our study, three statins were tested: the fermentationderived lovastatin, the semi-synthetic simvastatin and the synthetic fluvastatin. In previous studies, the tested Zygomycetes showed variable susceptibilities against the different statins (Lukács et al 2004;Chamilos et al 2006;Galgóczy et al 2007), although effects of simvastatin and fluvastatin on Mucor have not been examined until the present study. In our tests, complete blockage of growth was not achieved with the tested concentrations.…”

“…Although it is not easy to compare the results of the different studies because of differences in the applied test methods and the involved strains but it is worth to mention that similar sensitivity to lovastatin was detected in the cases of two M. circinelloides strains by Chamilos et al (2006); those strains were moderately sensitive to lovastatin with MICs of 32 and 56 lg ml -1 , respectively.…”

Posaconazole Enhances the Activity of Amphotericin B against Hyphae of Zygomycetes In Vitro

“…Interestingly, combination therapies have all been shown to be effective against zygomycete infection in vitro and did not exert antagonism (3,6,10).…”

Antifungal Activity of Colistin against Mucorales Species In Vitro and in a Murine Model of Rhizopus oryzae Pulmonary Infection

“…The fractional inhibitory concentration index (FICI) was calculated for checkerboard plates; values were interpreted as follows: FICI Յ 0.5, synergy; 0.5 Յ FICI Ͻ 4, indifference; and FICI Ͼ 4, antagonism (3,18).…”