Evolution of drug resistance in an antifungal-naive chronic Candida lusitaniae infection

Abstract

SignificanceDrug-resistant subpopulations of microbes or tumor cells are difficult to detect but can confound disease treatment. In this deep characterization of a chronic fungal infection, we report unprecedented heterogeneity in the drug resistance-related gene MRR1 among Clavispora (Candida) lusitaniae isolates from a single individual. Cells expressing Mrr1 variants that led to drug resistance, by elevated expression of the MDR1-encoded efflux protein, were present at low levels in each sample and thus were undetected in standard assays. We provide evidence that these drug-resistant fungi may arise indirectly in response to other factors present in the infection. Our work suggests that alternative methods may be able to identify drug-resistant subpopulations and thus positively impact patient care.

Comparative genomics for the elucidation of multidrug resistance (MDR) inCandida lusitaniae

“…We provided genetic (knock-outs and reversion experiments) to support that the V668G substitution is a GOF mutation which stimulates MFS7 expression. These data are consistent with a recent study describing several MRR1 mutations associated with FLC resistance in C. lusitaniae , but not including the V668G GOF mutation (5). This mutation may lead to the upregulation of several other genes and this hypothesis was confirmed here by RNAseq analysis of the P3 and P4 isolates.…”

“…A total of 18 non-synonymous SNPs were observed, among which 13 were unique. We counted 166 SNPs/indel in intergenic sequences between the isolates and 14 other indels in ORFs, some of them (5) causing unique frameshifts and truncations (File S3).…”

“…(27, 28). Recently, a study reported the analysis of 20 different C. lusitaniae isolates from a patient with cystic fibrosis (5). The study reported 404 inter-isolate SNPs (among which 45% were NSS) and 536 indels in total.…”

“…Interestingly, our data matches well with those comparing an azole-resistant with an azole-susceptible C. lusitaniae isolate. From the 19 identified regulated genes in this work (5), 12 were corresponding in our data set, and MDR1 was one among them (File S4).…”

“…Flucytosine resistance has also been described in C. lusitaniae and is associated with defects in cytosine permease (4). Recently, C. lusitaniae resistance to fluconazole was reported in the lungs of cystic fibrosis patients, even in the absence of a specific treatment with this drug (5). Simultaneous resistance to AmB and fluconazole was described in a patient treated intermittently with the two agents (6).…”