Inhibition of RNA Synthesis as a Therapeutic Strategy against Aspergillus and Fusarium : Demonstration of In Vitro Synergy between Rifabutin and Amphotericin B

We investigated the in vitro antifungal activity of amphotericin B, alone and in combination with rifabutin, an inhibitor of bacterial RNA polymerase, against 26 clinical isolates ofAspergillus and 25 clinical isolates ofFusarium . Synergy or additivism between these drugs was demonstrated against all isolates tested. Amphotericin B MICs were reduced upon combination with rifabutin from a mean of 0.65 μg/ml to a mean of 0.16 μg/ml againstAspergillus , and from a mean of 0.97 μg/ml to a mean of 0.39 μg/ml againstFusarium (P 32 μg/ml to a mean of 1.1 μg/ml against both fungi (P < 0.1 for both). These positive interactions were corroborated by a colony count study with twoFusarium isolates, for which treatment with the combination of subinhibitory concentrations of amphotericin B (at concentrations 2- and 4-fold less than the MIC) and rifabutin (at concentrations ranging from 4- to 64-fold less than the MIC) resulted in 3.2-log reductions in colony counts compared to those after treatment with either drug alone. Inhibition of RNA synthesis was shown to be the mechanism of antifungal activity. These results suggest that inhibition of fungal RNA synthesis might be a potential target for antifungal therapy.