AI Insight
This study investigated how chromosome number affects the evolution of drug resistance in the fungal pathogen Candida glabrata by comparing haploid (single chromosome set) and diploid (double chromosome set) strains exposed to the antifungal drug fluconazole. At moderate drug concentrations, both forms developed resistance through PDR1 mutations, but diploids additionally acquired heterozygous mutations in ERG11 and ERG25 genes and showed higher rates of aneuploidy (abnormal chromosome numbers). At high fluconazole concentrations, haploids and diploids evolved resistance through completely different genetic pathways, with diploids achieving higher resistance levels through heterozygous ERG25 mutations combined with multiple chromosome duplications.
Why it matters
Understanding how ploidy influences resistance evolution could help predict and potentially combat antifungal drug resistance in clinical settings. Since C. glabrata is a major cause of fungal infections in humans and can exist in both haploid and diploid states, these findings suggest that diploid strains may pose a greater therapeutic challenge due to their ability to develop higher resistance levels through distinct evolutionary pathways.
Understand the Science
⚠️ Preprint – Noch nicht peer-reviewed
Dieser Artikel wurde noch nicht von unabhängigen Experten begutachtet. Die Ergebnisse sind vorläufig und sollten mit Vorsicht interpretiert werden.
C. glabrata (syn. Nakaseomyces glabratus) is a major fungal pathogen, typically isolated as a haploid but occasionally found in diploid form. We isolated a spontaneous diploid variant of the type strain CBS138 and performed experimental evolution under fluconazole. At physiologically relevant concentrations of fluconazole, we found that haploids and diploids both acquired PDR1 mutations, as is commonly observed in C. glabrata. Diploids additionally acquired heterozygous ERG11 and ERG25 mutations, and were more likely to acquire aneuploidies. Despite an ancestral fitness advantage for haploids, after ~200 generations the highest-fitness clone, as measured in competitive assays with and without fluconazole, was a diploid PDR1 V329F/+ ERG11 K152E/+ double heterozygote. Diploid clones also had higher MICs. In a follow-up experiment in which we rapidly increased the fluconazole concentration to ~1 mg/mL, haploids and diploids adapted via entirely different paths: haploids via co-mutation in ERG3 and CgOSH3, a previously unreported path to fluconazole resistance, and diploids via heterozygous mutation in ERG25 coupled with trisomies of chrF, chrG, and chrI (in all clones) and chrC (in most).
Source: Diploidy alters the path of fluconazole adaptation in C. glabrata
Want to understand the basics behind this research?