Genomic Features Associated with the Degree of Phenotypic Resistance to Carbapenems in Carbapenem-Resistant Klebsiella pneumoniae.
Genomic Features Associated with the Degree of Phenotypic Resistance to Carbapenems in Carbapenem-Resistant Klebsiella pneumoniae.
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DOI：
10.1128/msystems.00194-21
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发表时间：
2021-10-26
期刊：
影响因子：
6.4
通讯作者：
Hauser AR
中科院分区：
文献类型：
--
作者：
Bulman ZP;Krapp F;Pincus NB;Wenzler E;Murphy KR;Qi C;Ozer EA;Hauser AR
耐碳青霉烯类肺炎克雷伯菌菌株会引起难以治疗的严重感染。碳青霉烯酶（例如肺炎克雷伯菌碳青霉烯酶（KPC））的产生是这些菌株抵抗碳青霉烯类杀伤的常见机制。然而，具有相似碳青霉烯酶基因的分离株之间的表型碳青霉烯类耐药性（MIC）程度可能存在显着差异，这表明我们对碳青霉烯类耐药性潜在机制的理解仍然不完整。为了解决这个问题，我们确定了 166 个对美罗培南、亚胺培南或厄他培南耐药的肺炎克雷伯菌临床分离株的全基因组序列。对主要含有 blaKPC-3 序列类型 258 (ST258) 分离株的多元线性回归分析表明，blaKPC 拷贝数和一些外膜孔蛋白基因突变与碳青霉烯类较高的 MIC 相关。 Tn4401 d 同工型携带的 blaKPC 基因也观察到了 MIC 升高的趋势。相比之下，ompK37 突变与较低的碳青霉烯类 MIC 相关，而广谱 β-内酰胺酶基因与耐碳青霉烯类肺炎克雷伯菌的较高或较低 MIC 无关。基于这些分离株全基因组序列的机器学习方法并没有显着改善对高或低 MIC 分离株的预测。这些结果建立在先前的发现之上，表明多种因素影响碳青霉烯类耐药肺炎克雷伯菌分离株的总体碳青霉烯类耐药水平。重要性 肺炎克雷伯菌可引起血液、尿路和肺部的严重感染。肺炎克雷伯菌对碳青霉烯类抗生素的耐药性是一个紧迫的公共卫生威胁，因为它会使这些分离株难以治疗。虽然已经研究了肺炎克雷伯菌中碳青霉烯类耐药性的个体因素，但很少有报告探讨它们在临床分离株中的综合影响。我们对 166 个临床碳青霉烯类耐药肺炎克雷伯菌分离株进行了测序，以评估已知基因对碳青霉烯类 MIC 的贡献，并尝试识别与较高碳青霉烯类 MIC 相关的新基因。 blaKPC 拷贝数和一些外膜孔蛋白基因突变与较高的碳青霉烯类 MIC 相关。相比之下，一种特定孔蛋白 ompK37 的突变与较低的碳青霉烯类 MIC 相关。机器学习并没有导致碳青霉烯类耐药性预测的实质性改善，也没有识别出与碳青霉烯类耐药性相关的新基因。这些发现增强了我们对肺炎克雷伯菌碳青霉烯类耐药性的许多影响因素的理解。
Carbapenem-resistant Klebsiella pneumoniae strains cause severe infections that are difficult to treat. The production of carbapenemases such as the K. pneumoniae carbapenemase (KPC) is a common mechanism by which these strains resist killing by the carbapenems. However, the degree of phenotypic carbapenem resistance (MIC) may differ markedly between isolates with similar carbapenemase genes, suggesting that our understanding of the underlying mechanisms of carbapenem resistance remains incomplete. To address this problem, we determined the whole-genome sequences of 166 K. pneumoniae clinical isolates resistant to meropenem, imipenem, or ertapenem. Multiple linear regression analysis of this collection of largely blaKPC-3-containing sequence type 258 (ST258) isolates indicated that blaKPC copy number and some outer membrane porin gene mutations were associated with higher MICs to carbapenems. A trend toward higher MICs was also observed with those blaKPC genes carried by the d isoform of Tn4401. In contrast, ompK37 mutations were associated with lower carbapenem MICs, and extended spectrum β-lactamase genes were not associated with higher or lower MICs in carbapenem-resistant K. pneumoniae. A machine learning approach based on the whole-genome sequences of these isolates did not result in a substantial improvement in prediction of isolates with high or low MICs. These results build upon previous findings suggesting that multiple factors influence the overall carbapenem resistance levels in carbapenem-resistant K. pneumoniae isolates. IMPORTANCE Klebsiella pneumoniae can cause severe infections in the blood, urinary tract, and lungs. Resistance to carbapenems in K. pneumoniae is an urgent public health threat, since it can make these isolates difficult to treat. While individual contributors to carbapenem resistance in K. pneumoniae have been studied, few reports explore their combined effects in clinical isolates. We sequenced 166 clinical carbapenem-resistant K. pneumoniae isolates to evaluate the contribution of known genes to carbapenem MICs and to try to identify novel genes associated with higher carbapenem MICs. The blaKPC copy number and some outer membrane porin gene mutations were associated with higher carbapenem MICs. In contrast, mutations in one specific porin, ompK37, were associated with lower carbapenem MICs. Machine learning did not result in a substantial improvement in the prediction of carbapenem resistance nor did it identify novel genes associated with carbapenem resistance. These findings enhance our understanding of the many contributors to carbapenem resistance in K. pneumoniae.