SANGLARD D, ISCHER F, BILLE J; Interscience Conference on Antimicrobial Agents and Chemotherapy (42nd : 2002 : San Diego, Calif.).
Abstr Intersci Conf Antimicrob Agents Chemother Intersci Conf Antimicrob Agents Chemother. 2002 Sep 27-30; 42: abstract no. M-221.
Univ. Hosp. Lausanne, Switzerland
RVZ is a new azole derivative with promising properties for the treatment of fungal infections. Since RVZ belongs to the class of azole antifungal agents, the development of resistance to this compound could potentially occur by mechanisms already operating in Candida albicans clinical strains resistant to other azole derivatives. Two of these mechanisms (multidrug efflux transport and alteration of affinity to the target of azoles, the cytochrome P450 CYP51A1) were thus tested in different systems with RVZ. The expression of C. albicans multidrug efflux transporters (ABC-transporters CDR1 and CDR2 and Major Facilitator CaMDR1) in Saccharomyces cerevisiae conferred resistance to RVZ suggesting that RVZ could be used as a substrate for these transporters. Accordingly, C. albicans deletion mutants of these genes showed increased susceptibility to RVZ as compared to wild type parents. The affinity of RVZ C. albicans CYP51A1 was estimated by an in vitro assay using S. cerevisiae expressing distinct proteins with different mutations (F405S, G464S, R467K, Y132H). Mutant CYP51A1 proteins, the genes of which were cloned from azole resistant isolates, showed different levels of affinity to known azole derivatives (fluconazole, itraconazole). We could observe that changes of affinity to RVZ for specific CYP51A1 mutant proteins paralleled those measured for fluconazole. Our studies conclude that RVZ showed typical properties shared by other azoles with respect to their capacity to be substrates for multidrug efflux transporters and to bind to CYP51A1 mutant proteins. Clinical C. albicans isolates with known azole resistance mechanisms were also tested for their susceptibility to RVZ. RVZ MICs increased to a similar extent as with other azoles, but since the initial values were lower, complete resistance may not be seen. However, a typical cross-resistance pattern was shown expected from the interactions of RVZ with multidrug transporters and with mutations in CYP51A1.
Publication Types:
Keywords:
- ATP-Binding Cassette Transporters
- Antifungal Agents
- Azoles
- Candida albicans
- Cytochrome P-450 Enzyme System
- ER 30346
- Fluconazole
- In Vitro
- Itraconazole
- Membrane Transport Proteins
- Microbial Sensitivity Tests
- Mycoses
- Saccharomyces cerevisiae
- Thiazoles
Other ID:
UI: 102267577
From Meeting Abstracts