Evolution of drug resistance in an antifungal-naive chronic Candida lusitaniae infection.
Evolution of drug resistance in an antifungal-naive chronic Candida lusitaniae infection.
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DOI：
10.1073/pnas.1807698115
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发表时间：
2018-11-20
影响因子：
11.1
通讯作者：
Hogan DA
中科院分区：
文献类型：
--
作者：
Demers EG;Biermann AR;Masonjones S;Crocker AW;Ashare A;Stajich JE;Hogan DA
微生物或肿瘤细胞的耐药亚群很难检测，但可能会影响疾病治疗。在对慢性真菌感染的深入表征中，我们报告了来自单个个体的棒孢菌（念珠菌）分离株中耐药相关基因 MRR1 的前所未有的异质性。表达 Mrr1 变体的细胞通过 MDR1 编码的外排蛋白的表达升高而导致耐药性，在每个样品中以低水平存在，因此在标准测定中未检测到。我们提供的证据表明，这些耐药真菌可能是由于感染中存在的其他因素而间接产生的。我们的工作表明，替代方法可能能够识别耐药亚群，从而对患者护理产生积极影响。对目前可用的有限数量的抗菌药物的管理需要识别含有耐药菌株的感染，并发现促进耐药性进化的因素。在这里，我们报告了一种单一的真菌感染，其中我们已经确定了许多亚群，这些亚群的影响耐药性的单个基因的等位基因有所不同。该基因座的多样性明显大于报道的细菌感染中赋予抗生素耐药性的等位基因的异质性。通过对来自单个囊性纤维化个体的数百个Clavispora（Candida）lusitaniae分离株的基因组进行分析，发现MRR1中至少有25个非同义突变，MRR1编码能够在念珠菌属物种中诱导氟康唑（FLZ）耐药性的转录因子。由于 MDR1 编码的外排泵表达升高，具有高活性 Mrr1 变体的分离株对 FLZ 具有抗性。我们发现Mrr1调节的Mdr1高活性可以保护宿主免受宿主和细菌因素的影响，这表明可以间接选择耐药性，并可能解释该先前未接触过唑类药物的个体的Mrr1异质性。对右肺上叶和下叶的 C. lusitaniae 种群进行的区域分析表明，整个亚种群存在混合。我们通过合并测序对痰和肺群体进行回顾性表征，发现赋予 FLZ 抗性的等位基因在每个池中只占少数，这可能解释了为什么它们在 FLZ 治疗不成功之前未被检测到。新的药敏试验方案可以检测异质单物种感染中存在问题的耐药亚群。
Drug-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. Management of the limited number of antimicrobials currently available requires the identification of infections that contain drug-resistant isolates and the discovery of factors that promote the evolution of drug resistance. Here, we report a single fungal infection in which we have identified numerous subpopulations that differ in their alleles of a single gene that impacts drug resistance. The diversity at this locus was markedly greater than the reported heterogeneity of alleles conferring antibiotic resistance in bacterial infections. Analysis of genomes from hundreds of Clavispora (Candida) lusitaniae isolates, through individual and pooled isolate sequencing, from a single individual with cystic fibrosis revealed at least 25 nonsynonymous mutations in MRR1, which encodes a transcription factor capable of inducing fluconazole (FLZ) resistance in Candida species. Isolates with high-activity Mrr1 variants were resistant to FLZ due to elevated expression of the MDR1-encoded efflux pump. We found that high Mrr1-regulated Mdr1 activity protected against host and bacterial factors, suggesting drug resistance can be selected for indirectly and perhaps explaining the Mrr1 heterogeneity in this individual who had no prior azole exposure. Regional analysis of C. lusitaniae populations from the upper and lower lobes of the right lung suggested intermingling of subpopulations throughout. Our retrospective characterization of sputum and lung populations by pooled sequencing found that alleles that confer FLZ resistance were a minority in each pool, possibly explaining why they were undetected before unsuccessful FLZ therapy. New susceptibility testing regimes may detect problematical drug-resistant subpopulations in heterogeneous single-species infections.
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影响因子：
2.9
作者：
Ceesay, M. Mansour;Couchman, Lewis;Pagliuca, Antonio
通讯作者：
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3.7
作者：
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