FAVRE B, LEIDICH SD, GHANNOUM MA, RYDER NS; Interscience Conference on Antimicrobial Agents and Chemotherapy (41st : 2001 : Chicago, Ill.).
Abstr Intersci Conf Antimicrob Agents Chemother Intersci Conf Antimicrob Agents Chemother. 2001 Dec 16-19; 41: abstract no. J-1842.
Novartis Res. Inst., Vienna, Austria
BACKGROUND: Six sequential isolates of Trichophyton rubrum from a patient with onychomycosis who failed therapy with oral terbinafine had reduced susceptibility to terbinafine and related squalene epoxidase inhibitors, but not to other antifungal agents. To gain insight into the mechanism of resistance, the strains were investigated for abnormalities in ergosterol biosynthesis and its sensitivity to terbinafine. METHODS: Cellular ergosterol biosynthesis was measured by incorporation of [[14]C]acetate. Squalene epoxidase was measured in cell-free preparations by incorporation of labelled squalene into squalene epoxide and sterols. Lipids were analyzed by TLC and fractions were visualized and quantitated by radioactive imaging and scintillation counting. Direct comparison was made with a reference strain of T. rubrum (NFI 1895) in which squalene epoxidase was previously studied. RESULTS: All 6 resistant isolates displayed a normal pattern of cellular ergosterol biosynthesis, except for slight accumulation of radiolabelled squalene. In the normal strain NFI 1895, ergosterol biosynthesis was effectively eliminated by terbinafine at 0.03 microg/ml. However, ergosterol biosynthesis in the resistant isolates was only inhibited by terbinafine at >1 microg/ml (IC[50] c. 5 microg/ml). There was no significant difference in sensitivity between the 6 resistant isolates. Squalene epoxidase from the resistant strains was less active than normal, and was 4 orders of magnitude less sensitive to terbinafine than that from a normal strain (IC[50] c. 50 microg/ml and 0.005 microg/ml respectively). CONCLUSION: this first reported example of resistance to terbinafine in T. rubrum involves loss of sensitivity at the target enzyme level, probably due to mutation in the squalene epoxidase gene.
Publication Types:
Keywords:
- Antifungal Agents
- Arthrodermataceae
- Enzyme Inhibitors
- Ergosterol
- Humans
- Naphthalenes
- Oxygenases
- Squalene
- Sterols
- Trichophyton
- terbinafine
Other ID:
UI: 102268530
From Meeting Abstracts