Synergic effect of simvastatin in combination with amphotericin B against environmental strains of Cryptococcus neoformans from northeastern Brazil: a prospective experimental study

Abstract

BACKGROUND: Statins are used as cholesterol-lowering drugs and may also have direct antimicrobial effects. OBJECTIVE: To evaluate synergic interactions between simvastatin and both amphotericin B and fluconazole, against environmental strains of Cryptococcus neoformans isolated from captive birds’ droppings. DESIGNAND SETTING: Experimental study conducted at Federal University of Piauí, Parnaíba, in collaboration with Federal University of Triângulo Mineiro, Uberaba, Brazil. METHODS: Statin susceptibility tests of Cryptococcus neoformans samples were performed as prescribed in standards. Interactions of simvastatin with amphotericin and fluconazole were evaluated using the checkerboard microdilution method. Presence of these interactions was quantitatively detected through determining the fractional inhibitory concentration index (FICI). RESULTS: Isolates of Cryptococcus neoformans were obtained from 30 of the 206 samples of dry bird excreta (14.5%) that were collected from pet shops and houses. Ten isolates were selected for susceptibility tests. All of them were susceptible to amphotericin and fluconazole. All presented minimum inhibitory concentration (MIC) > 128 µg/ml and, thus, were resistant in vitro to simvastatin. An in vitro synergic effect was shown through combined testing of amphotericin B and simvastatin, such that six isolates (60%) presented FICI < 0.500. Two isolates showed considerable reductions in MIC, from 1 µg/ml to 0.250 µg/ml. No synergic effect was observed through combining fluconazole and simvastatin. CONCLUSION: These results demonstrate that simvastatin should be considered to be a therapeutic alternative, capable of potentiating the action of amphotericin B. However, further studies are necessary to clarify the real effect of simvastatin as an antifungal agent.

Drug repurposing strategies in the development of potential antifungal agents

“… 62.5–1000 - AmB, ITR, FLC Inhibits ergosterol synthesis. Silva et al ( 2020 ) Saccharomyces cerevisiae 40 - CTZ, ITR, MIA Inhibits ergosterol synthesis. Cabral et al ( 2013 ) Paecilomyces variotii 8 - - - Nyilasi et al ( 2010 ) Rhizopus oryzae 64 - - - Nyilasi et al ( 2010 ) A. fumigatus 6.25 - FLC - Nyilasi et al ( 2010 ) Pravastatin C. albicans No effects.…”

“… Nash et al ( 2002 ) Atorvastatin C. albicans 16–256 G. mellonella MIA Inhibits ergosterol synthesis. Nyilasi et al ( 2010 ); Ajdidi et al ( 2019 ); Esfahani et al ( 2019 ) C. glabrata 4–64 - FLC - Nyilasi et al ( 2010 ); Esfahani et al ( 2019 ); Lima et al ( 2019 ) C. utilis 200 - - - Silva et al ( 2020 ) C. krusei 8 - - - Esfahani et al ( 2019 ) C. kefyr 4-16 - - - Esfahani et al ( 2019 ) Cryptococcus gattii ≥ 256 Mice FLC (I) Inhibits ergosterol synthesis; (II) Induces the production of ROS. Chin et al ( 1997 ); Ribeiro et al ( 2017 ) Saccharomyces cerevisiae 40 - CTZ, ITR, MIA - Cabral et al ( 2013 ) C. stellatoidea 16 - …”