Two Sequential Clinical Isolates of <i>Candida glabrata</i> with Multidrug-Resistance to Posaconazole and Echinocandins

• Main Authors: Qiqi Wang (Author), Yun Li (Author), Xuan Cai (Author), Ruoyu Li (Author), Bo Zheng (Author), Ence Yang (Author), Tianyu Liang (Author), Xinyu Yang (Author), Zhe Wan (Author), Wei Liu (Author)
• Format: Book
• Published: MDPI AG, 2021-10-01T00:00:00Z.
• Subjects: article
• Online Access: Connect to this object online.
• Notes: 10.3390/antibiotics10101217; 2079-6382
• Keywords: <i>Candida glabrata</i>; multidrug-resistance; echinocandins; triazoles; posaconazole; FK520; Therapeutics. Pharmacology; RM1-950
• Source: Antibiotics, Vol 10, Iss 10, p 1217 (2021)

<i>Candida glabrata</i> is one of the most prevalent causative pathogens of invasive candidiasis, and multidrug-resistant strains are emerging. We identified two clinical isolates of <i>C. glabrata</i>, BMU10720 and BMU10722 sequentially isolated from one patient with multidrug-resistance to posaconazole (POS), caspofungin (CAS), micafungin (MCF), and anidulafungin (ANF). Overexpression of <i>ERG11</i> in BMU10720 and <i>CDR1</i> in BMU10722 were detected at basal level. When exposed to POS, <i>CDR1</i> was significantly up-regulated in both isolates compared with susceptible reference strain, while <i>ERG11</i> was up-regulated considerably only in BMU10720. <i>PDR1</i> sequencing revealed that both isolates harbored P76S, P143T, and D243N substitutions, while <i>ERG11</i> was intact. Cdr1 inhibitor FK520 reversed POS-resistance by down-regulating <i>ERG11</i> expression. <i>FKS</i> sequencing revealed that both isolates harbored S663P substitution in <i>FKS2</i>, and four single nucleotide polymorphisms (SNPs) existed in <i>FKS2</i> genes between BMU10720 and BMU10722, while <i>FKS1</i> was intact. Both <i>FKS1</i> and <i>FKS2</i> were up-regulated by CAS in BMU10720 and BMU10722. FK520 down-regulated <i>FKS2</i> expression induced by CAS through inhibiting calcineurin, resulting in synergic effect with echinocandins as well as Congo Red and Calcofluor White, two cell wall-perturbing agents. In conclusion, the multidrug-resistance of <i>C. glabrata</i> isolates in our study was conferred by different mechanisms. <i>CDR1</i> and <i>ERG11</i> overexpression in one isolate and only <i>CDR1</i> overexpression in the other isolate may mediate POS-resistance. S663P mutation in <i>FKS2</i> and up-regulation of <i>FKS2</i> may contribute to echinocandin-resistance in both isolates.