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 of Aspergillus and 25 clinical isolates of Fusarium. 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 microg/ml to a mean of 0.16 microg/ml against Aspergillus, and from a mean of 0.97 microg/ml to a mean of 0.39 microLg/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 microg/ml to a mean of 1.1 microg/ml against both fungi (P < 0.000001 for both). These positive interactions were corroborated by a colony count study with two Fusarium 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.
Clancy
C J
CJ
Department of Medicine, University of Florida College of Medicine, and the Veterans Affairs Medical Center, Gainesville 32610, USA.
Yu
Y C
YC
Lewin
A
A
Nguyen
M H
MH
D000666:Amphotericin B / Q000494:pharmacology*; D001230:Aspergillus / Q000187:drug effects* / Q000235:genetics; D004357:Drug Synergism; D004359:Drug Therapy, Combination / Q000494:pharmacology*; D005656:Fungal Proteins / Q000187:drug effects; D005670:Fusarium / Q000187:drug effects* / Q000235:genetics; D006801:Humans; D008826:Microbial Sensitivity Tests; D012331:RNA, Fungal / Q000096:biosynthesis / Q000187:drug effects*; D017828:Rifabutin / Q000494:pharmacology*
D005656:Fungal Proteins; D012331:RNA, Fungal; D017828:Rifabutin; D000666:Amphotericin B