title: 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 (MIC50, 48.0 microg/ml; 50% minimal fungicidal concentration, 56.0 microg/ml; 50% effective concentration, 29.4 microg/ml [6.6 to 38.9 microg/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.
authors.affiliation: Department of Infectious Diseases, Infection Control, and Employee Health, Unit 402, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd., Houston, Texas 77030, USA.
authors.forename: Georgios
authors.initials: G
authors.lastname: Chamilos
authors.forename: Russell E
authors.initials: RE
authors.lastname: Lewis
authors.forename: Dimitrios P
authors.initials: DP
authors.lastname: Kontoyiannis
mesh_terms: D000818:Animals; D000935:Antifungal Agents / Q000494:pharmacology*; D004357:Drug Synergism; D005658:Fungi / Q000187:drug effects* / Q000302:isolation & purification; D008148:Lovastatin / Q000494:pharmacology*; D008826:Microbial Sensitivity Tests / Q000379:methods; D009181:Mycoses / Q000382:microbiology; D011743:Pyrimidines / Q000494:pharmacology*; D014230:Triazoles / Q000494:pharmacology*; D065819:Voriconazole
chemical_list: D000935:Antifungal Agents; D011743:Pyrimidines; D014230:Triazoles; D008148:Lovastatin; D065819:Voriconazole