Loss of C-5 Sterol Desaturase Activity in Candida albicans: Azole Resistance or Merely Trailing Growth?
Loss of C-5 Sterol Desaturase Activity in Candida albicans: Azole Resistance or Merely Trailing Growth?
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DOI：
10.1128/aac.01337-18
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发表时间：
2019-01-01
影响因子：
4.9
通讯作者：
Palmer, Glen E.
中科院分区：
文献类型：
--
作者：
Luna-Tapia, Arturo;Butts, Arielle;Palmer, Glen E.
药物外排泵的表达增加和靶酶Erg 11 p的变化已知有助于白色念珠菌（最流行的真菌病原体之一）的唑类耐药。编码固醇δ（5，6）-去饱和酶的EERG 3的突变也赋予体外唑类抗性。然而，目前还不清楚Erg 3 p活性的丧失是否足以在哺乳动物宿主中产生耐药性，并且在唑类耐药临床分离株中报道了相对较少的Erg 3突变体。拖尾生长（在唑类存在下的残留生长）是许多C.白色念珠菌分离物，并且在其极端形式下，可被误认为耐药性。本研究的目的是确定Erg 3 p缺陷的C.在唑类化合物存在下的白念珠菌突变体具有唑类化合物抗性或夸大形式的拖尾生长的特征。我们的研究结果表明，类似于尾随分离株，erg 3三角洲/三角洲突变体的能力，以忍受唑类暴露的后果至少部分依赖于温度和pH值。这与真正的唑类耐药性，结果从增强药物外排和/或目标酶的变化。erg 3 Delta/Delta突变体和拖尾分离株在唑类处理后似乎也维持显著的膜损伤，进一步将它们与抗性分离株区分开。然而，erg 3 Delta/Delta突变体对唑类的不敏感性不受钙调磷酸酶抑制剂环孢菌素A的影响，从而将其与拖尾分离株区分开来。总之，erg 3突变体表型在定性和定量上都不同于唑类抗性和拖尾生长。
Increased expression of drug efflux pumps and changes in the target enzyme Erg11p are known to contribute to azole resistance in Candida albicans, one of the most prevalent fungal pathogens. Mutations that inactivate ERG3, which encodes sterol Delta(5,6)-desaturase, also confer in vitro azole resistance. However, it is unclear whether the loss of Erg3p activity is sufficient to confer resistance within the mammalian host, and relatively few erg3 mutants have been reported among azole-resistant clinical isolates. Trailing growth (residual growth in the presence of the azoles) is a phenotype observed with many C. albicans isolates and, in its extreme form, can be mistaken for resistance. The purpose of this study was to determine whether the growth of Erg3p-deficient C. albicans mutants in the presence of the azoles possesses the characteristics of azole resistance or of an exaggerated form of trailing growth. Our results demonstrate that, similar to trailing isolates, the capacity of an erg3 Delta/Delta mutant to endure the consequences of azole exposure is at least partly dependent on both temperature and pH. This contrasts with true azole resistance that results from enhanced drug efflux and/or changes in the target enzyme. The erg3 Delta/Delta mutant and trailing isolates also appear to sustain significant membrane damage upon azole treatment, further distinguishing them from resistant isolates. However, the insensitivity of the erg3 Delta/Delta mutant to azoles is unaffected by the calcineurin inhibitor cyclosporin A, distinguishing it from trailing isolates. In conclusion, the erg3 mutant phenotype is qualitatively and quantitatively distinct from both azole resistance and trailing growth.