Research of Mrr1, Cap1 and MDR1 in Candida albicans resistant to azole medications

Abstract

The aim of the present study was to investigate the association between Mrr1, adenylyl cyclase-associated protein 1 (Cap1) and multi-drug resistance gene 1 (MDR1), and to assess the mutations in Mrr1 and Cap1 in azole-resistant Candida albicans strains. The study isolated 68 C. albicans strains from patients with vulvovaginal candidiasis. Drug susceptibility testing was conducted to characterize the resistance profile of these strains to fluconazole, itraconazole and voriconazole. Polymerase chain reaction (PCR) amplification was performed for Cap1 and Mrr1, and the PCR products were sequenced to identify any mutations. Reverse transcription-quantitative PCR was performed to measure Cap1, Mrr1 and MDR1 mRNA in C. albicans strains. The results of the present study indicated S381N, P311S and A390T missense mutations in Cap1 and T917M, T923I, N937K, E1020Q, F1032L and S1037L missense mutations in Mrr1 in azole-resistant C. albicans strains. Fluconazole-resistant strains had significantly elevated Cap1 and MDR1 mRNA levels compared with fluconazole-sensitive strains (P<0.01). The mRNA levels of Cap1, Mrr1 and MDR1 were significantly increased in the strains resistant to all three of fluconazole, itraconazole and voriconazole compared with strains sensitive to the three agents (P<0.001, P=0.037 and P<0.001, respectively). Cap1 expression was positively correlated with MDR1 expression in fluconazole-resistant strains (P<0.05). No significant correlation was observed between Cap1, Mrr1 and MDR1 in the strains resistant to fluconazole, itraconazole or voriconazole. The results of the present study suggested that fluconazole resistance may involve MDR1 overexpression mediated by Cap1 overexpression. Cross-resistance between fluconazole, itraconazole and voriconazole may be associated with mutations in Cap1 and Mrr1, rather than their overexpression. In addition, the present study also revealed two novel mutations in Mrr1; T917M and T923I. These findings may provide a basis for elucidating the molecular mechanisms of and improving therapeutic treatments to tackle azole resistance.

Mechanisms of action of antimicrobial peptides ToAP2 and NDBP-5.7 against Candida albicans planktonic and biofilm cells

“…This disease has a close association with health-care environment where is a major cause of morbidity and mortality specially among elderly and premature babies 88,89 . As for other invasive fungal infections the available therapeutic options are extremely limited and associated with high toxicity, costs and the increase in fungal strains resistant to the few antifungal drugs currently available, such echinocandins and azoles [90][91][92][93] .…”

<p>The Long Noncoding RNA ZFAS1 Potentiates the Development of Hepatocellular Carcinoma via the microRNA-624/MDK/ERK/JNK/P38 Signaling Pathway</p>

“…RNAiso Plus (TAKARA, Otsu, Shiga, Japan) 14 and Trizol LS Reagent (TAKARA, Otsu, Shiga, Japan) kits were used to extract total RNA from HCC tissues and cells, respectively. The reliability of the obtained RNA was verified by the formaldehyde denaturing agarose gel electrophoresis.…”

An Overview on Conventional and Non-Conventional Therapeutic Approaches for the Treatment of Candidiasis and Underlying Resistance Mechanisms in Clinical Strains

“…The overexpression of drug-efflux pump-encoding genes results, in many cases, from the occurrence of activating mutations in the coding sequence of the corresponding regulators [41,45,78,82,[85][86][87][88][89]. This type of mechanism has been documented for CgPdr1 in C. glabrata; for CaTac1, CaMrr1 and CaUpc2 in C. albicans and for CpMrr1 and CpTac1 in C. parapsilosis [41,45,78,82,85,88].…”

“…Summary of the mechanisms of resistance registered in azole-resistant Candida isolates, as described in[40][41][42][43]72,[76][77][78][79]82,[85][86][87][88][89]92,93,96,[111][112][113][114][115][116][117][118][119][120][121][122][123][124][125][126][127][128].…”