Wang Qiqi, Li Yun, Cai Xuan, Li Ruoyu, Zheng Bo, Yang Ence, Liang Tianyu, Yang Xinyu, Wan Zhe, Liu Wei
Department of Dermatology and Venerology, Peking University First Hospital, Beijing 100034, China.
National Clinical Research Center for Skin and Immune Diseases, Beijing 100034, China.
Antibiotics (Basel). 2021 Oct 7;10(10):1217. doi: 10.3390/antibiotics10101217.
is one of the most prevalent causative pathogens of invasive candidiasis, and multidrug-resistant strains are emerging. We identified two clinical isolates of , BMU10720 and BMU10722 sequentially isolated from one patient with multidrug-resistance to posaconazole (POS), caspofungin (CAS), micafungin (MCF), and anidulafungin (ANF). Overexpression of in BMU10720 and in BMU10722 were detected at basal level. When exposed to POS, was significantly up-regulated in both isolates compared with susceptible reference strain, while was up-regulated considerably only in BMU10720. sequencing revealed that both isolates harbored P76S, P143T, and D243N substitutions, while was intact. Cdr1 inhibitor FK520 reversed POS-resistance by down-regulating expression. sequencing revealed that both isolates harbored S663P substitution in , and four single nucleotide polymorphisms (SNPs) existed in genes between BMU10720 and BMU10722, while was intact. Both and were up-regulated by CAS in BMU10720 and BMU10722. FK520 down-regulated 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 isolates in our study was conferred by different mechanisms. and overexpression in one isolate and only overexpression in the other isolate may mediate POS-resistance. S663P mutation in and up-regulation of may contribute to echinocandin-resistance in both isolates.
是侵袭性念珠菌病最常见的致病病原体之一，并且多重耐药菌株正在出现。我们鉴定了两株临床分离株，BMU10720和BMU10722，它们是从一名对泊沙康唑（POS）、卡泊芬净（CAS）、米卡芬净（MCF）和阿尼芬净（ANF）多重耐药的患者中依次分离得到的。在BMU10720中检测到[具体基因1]的过表达，在BMU10722中检测到[具体基因2]的过表达处于基础水平。当暴露于POS时，与敏感参考菌株相比，这两株分离株中[具体基因1]均显著上调，而[具体基因2]仅在BMU10720中大幅上调。[具体基因1]测序显示，两株分离株均携带P76S、P143T和D243N替换，而[具体基因2]完整。Cdr1抑制剂FK520通过下调[具体基因1]表达逆转了对POS的耐药性。[具体基因3]测序显示，两株分离株在[具体基因3]中均携带S663P替换，并且在BMU10720和BMU10722之间的[具体基因4]基因中存在四个单核苷酸多态性（SNP），而[具体基因5]完整。在BMU10720和BMU10722中，[具体基因6]和[具体基因7]均被CAS上调。FK520通过抑制钙调神经磷酸酶下调由CAS诱导的[具体基因6]表达，从而与棘白菌素以及两种细胞壁干扰剂刚果红和荧光增白剂产生协同作用。总之，我们研究中[具体菌株]分离株的多重耐药性是由不同机制导致的。一株分离株中[具体基因1]和[具体基因2]的过表达以及另一株分离株中仅[具体基因1]的过表达可能介导了对POS的耐药性。[具体基因3]中的S663P突变和[具体基因6]的上调可能导致两株分离株对棘白菌素耐药。
