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Antimicrobial Agents and Chemotherapy, March 1998, p. 509-513, Vol. 42, No. 3
0066-4804/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

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

Cornelius J. Clancy,1,3 Yue C. Yu,1 Alfred Lewin,2 and M. Hong Nguyen1,3,*

Division of Infectious Disease, Department of Medicine,1 and Department of Molecular Genetics and Microbiology,2 University of Florida College of Medicine, and the Veterans Affairs Medical Center,3 Gainesville, Florida

Received 19 May 1997/Returned for modification 15 August 1997/Accepted 8 December 1997

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 µg/ml to a mean of 0.16 µg/ml against Aspergillus, and from a mean of 0.97 µg/ml to a mean of 0.39 µg/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 µg/ml to a mean of 1.1 µg/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.

* Corresponding author. Mailing address: Department of Medicine, University of Florida College of Medicine, P.O. Box 100277, JHMHC, Gainesville, FL 32610. Phone: (352) 392-4058. Fax: (352) 392-6481. E-mail: nguyemt{at}medicine.ufl.edu.

Antimicrobial Agents and Chemotherapy, March 1998, p. 509-513, Vol. 42, No. 3
0066-4804/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.


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