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Drug resistance in the opportunistic pathogens Candida albicans and Candida glabrata
Abstract:
There are three major classes of antifungal drug used to treat patients suffering from topical and systemic infections caused by Candida albicans. Both the polyene macrolide antibiotics and the synthetic imidazole derivatives interact with membranes of sensitive organisms causing an impairment of function and cessation of growth. It is possible to obtain mutants of C. albicans resistant to these drugs but they are not a clinical problem. This may result from the fact that the organism is diploid with no haploid stage in its life cycle and the interaction of these compounds with their target is complex involving a number of membrane constituents. In contrast the occurrence of strains of C. albicans resistant to 5-fluorocytosine is a serious clinical problem. Here partial resistance is associated with heterozygosity at the locus coding for UMP pyrophosphorylase. Mitotic segregation can give rise to homozygous resistance in strains where the enzyme is completely absent. This is analogous to acyclovir resistance in herpes simplex virus where resistance is associated with loss of the virus encoded thymidine kinase.
Insights
Antifungal drug resistance in Candida albicans varies by drug class. While resistance to polyenes and imidazoles is rare, 5-fluorocytosine resistance is a significant clinical issue due to genetic mechanisms.
Area of Science:
- Mycology
- Medical Mycology
- Antimicrobial Resistance
Background:
- Candida albicans is a major cause of topical and systemic fungal infections.
- Antifungal drugs are crucial for treating these infections, with polyenes, imidazoles, and 5-fluorocytosine being key agents.
- Understanding drug resistance mechanisms is vital for effective treatment strategies.
Purpose of the Study:
- To compare the mechanisms and clinical significance of drug resistance in Candida albicans for different antifungal drug classes.
- To investigate the genetic basis of resistance to 5-fluorocytosine in Candida albicans.
Main Methods:
- Analysis of drug interaction with fungal membranes for polyene and imidazole antifungals.
- Genetic analysis of Candida albicans mutants resistant to 5-fluorocytosine, focusing on UMP pyrophosphorylase.
- Comparison with resistance mechanisms in other pathogens, such as acyclovir resistance in herpes simplex virus.
Main Results:
- Mutants of Candida albicans resistant to polyene macrolides and imidazole derivatives are not a significant clinical problem.
- Resistance to 5-fluorocytosine is a serious clinical issue in Candida albicans.
- Partial resistance to 5-fluorocytosine is linked to heterozygosity for UMP pyrophosphorylase, with homozygous resistance arising from enzyme absence.
Conclusions:
- The diploid nature and complex drug-target interactions of Candida albicans limit resistance to polyenes and imidazoles.
- The genetic mechanisms underlying 5-fluorocytosine resistance, involving UMP pyrophosphorylase, present a significant clinical challenge.
- Understanding these distinct resistance pathways is essential for developing new antifungal therapies.