title: Yeasts acquire resistance secondary to antifungal drug treatment by adaptive mutagenesis.
abstract: Acquisition of resistance secondary to treatment both by microorganisms and by tumor cells is a major public health concern. Several species of bacteria acquire resistance to various antibiotics through stress-induced responses that have an adaptive mutagenesis effect. So far, adaptive mutagenesis in yeast has only been described when the stress is nutrient deprivation. Here, we hypothesized that adaptive mutagenesis in yeast (Saccharomyces cerevisiae and Candida albicans as model organisms) would also take place in response to antifungal agents (5-fluorocytosine or flucytosine, 5-FC, and caspofungin, CSP), giving rise to resistance secondary to treatment with these agents. We have developed a clinically relevant model where both yeasts acquire resistance when exposed to these agents. Stressful lifestyle associated mutation (SLAM) experiments show that the adaptive mutation frequencies are 20 (S. cerevisiae -5-FC), 600 (C. albicans -5-FC) or 1000 (S. cerevisiae--CSP) fold higher than the spontaneous mutation frequency, the experimental data for C. albicans -5-FC being in agreement with the clinical data of acquisition of resistance secondary to treatment. The spectrum of mutations in the S. cerevisiae -5-FC model differs between spontaneous and acquired, indicating that the molecular mechanisms that generate them are different. Remarkably, in the acquired mutations, an ectopic intrachromosomal recombination with an 87% homologous gene takes place with a high frequency. In conclusion, we present here a clinically relevant adaptive mutation model that fulfils the conditions reported previously.
authors.affiliation: Unidad de Investigación. Hospital Universitario Nuestra Señora de Candelaria, Santa Cruz de Tenerife, Spain.
authors.forename: David
authors.initials: D
authors.lastname: Quinto-Alemany
authors.forename: Ana
authors.initials: A
authors.lastname: Canerina-Amaro
authors.forename: Luís G
authors.initials: LG
authors.lastname: Hernández-Abad
authors.forename: Félix
authors.initials: F
authors.lastname: Machín
authors.forename: Floyd E
authors.initials: FE
authors.lastname: Romesberg
authors.forename: Cristina
authors.initials: C
authors.lastname: Gil-Lamaignere
mesh_terms: D000935:Antifungal Agents / Q000494:pharmacology*; D001483:Base Sequence; D002176:Candida albicans / Q000187:drug effects* / Q000235:genetics; D002453:Cell Cycle; D004271:DNA, Fungal; D025141:Drug Resistance, Fungal / Q000235:genetics*; D016521:Electrophoresis, Gel, Pulsed-Field; D005434:Flow Cytometry; D008826:Microbial Sensitivity Tests; D008969:Molecular Sequence Data; D016296:Mutagenesis; D012441:Saccharomyces cerevisiae / Q000187:drug effects* / Q000235:genetics; D012689:Sequence Homology, Nucleic Acid
chemical_list: D000935:Antifungal Agents; D004271:DNA, Fungal