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, al one and in combination viith rifabutin, an inhibitor of bacterial RNA polymerase, against 26 clinical isolates of Aspergillus and 25 clinica l isolates of Fusarium. Synergy or additivism between these drugs was demonstrated against all isolates tested. Amphotericin B MICs were red uced upon combination with rifabutin from a mean of 0.65 mu g/ml to a mean of 0.16 mu g/ml against Aspergillus, and from a mean of 0.97 mu g /ml to a mean of 0.39 mu g/ml against Fusarium (P < 0.000001 for both) . Similarly, the MICs of rifabutin were reduced upon combination with amphotericin B from a mean of >32 mu g/ml to a mean of 1.1 mu g/ml aga inst both fungi (P < 0.000001 for both). These positive interactions w ere corroborated by a colony count study with two Fusarium isolates, f or which treatment with the combination of subinhibitory concentration s of amphotericin B (at concentrations 2- and 4-fold less than the MIG ) and rifabutin (at concentrations ranging from 4- to 64-fold less tha n the MIG) resulted in 3.2-log reductions in colony counts compared to those after treatment with either drug alone. Inhibition of RNA synth esis was shown to be the mechanism of antifungal activity. These resul ts suggest that inhibition of fungal RNA synthesis might be a potentia l target for antifungal therapy.