肺炎克雷伯氏菌对可乐定耐药性的遗传和结构基础:揭示分子机制。

IF 3.7 3区 医学 Q2 INFECTIOUS DISEASES Journal of global antimicrobial resistance Pub Date : 2024-07-17 DOI:10.1016/j.jgar.2024.06.019
Sahar Alousi , Jamal Saad , Balig Panossian , Rita Makhlouf , Charbel Al Khoury , Kelven Rahy , Sergio Thoumi , George F. Araj , Rony Khnayzer , Sima Tokajian
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引用次数: 0

摘要

背景:抗菌药耐药性(AMR)以及多重耐药性(MDR),主要在革兰氏阴性菌中呈上升趋势。随着全球耐药性的迅速出现,秋水仙素(多粘菌素 E)仍然是治疗 MDR 细菌感染的主要最后手段之一:由于细菌对可乐定耐药的确切机制仍未阐明,本研究有必要阐明耐碳青霉烯类(CR)肺炎克雷伯菌分离株对可乐定耐药和异耐药的潜在机制:方法:采用全基因组表征方法对耐药分离株进行分子分析,并对脂质 A 进行 MALDI-TOF MS 分析:结果:在 32 个 CR 肺炎克雷伯菌分离株中,有几个分离株对可乐定具有耐药性和中间耐药性。具有中间耐药性的 7 个分离株表现出 "跳井 "现象,这是因为存在耐药亚群。三个对可乐定完全耐药的分离物在 MALDI-TOF MS 上显示出 m/z 1840 和 1824 的离子,分别代表脂肪酰基链 C'-2 位有或没有羟基化的双磷酸化和六酰化脂质 A。研究 mgrB 基因座的遗传环境发现,在三个对秋水仙素耐药的分离物中,存在破坏 mgrB 基因座的插入序列:结论:我们的研究结果表明,通过控制脂质A分子的染色体调控网络突变和破坏mgrB基因的IS序列,可诱导产生对可乐定的耐药性/异耐药性,从而导致MIC值升高和治疗失败。应采用不同的治疗策略来避免与秋水仙素异抗性相关的治疗失败,主要是通过秋水仙素与碳青霉烯类、氨基糖苷类或替加环素联合治疗。
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Genetic and structural basis of colistin resistance in Klebsiella pneumoniae: Unravelling the molecular mechanisms

Objective

Antimicrobial resistance (AMR), together with multidrug resistance (MDR), mainly among Gram-negative bacteria, has been on the rise. Colistin (polymyxin E) remains one of the primary available last resorts to treat infections caused by MDR bacteria during the rapid emergence of global resistance. As the exact mechanism of bacterial resistance to colistin remains undetermined, this study warranted elucidation of the underlying mechanisms of colistin resistance and heteroresistance among carbapenem-resistant Klebsiella pneumoniae isolates.

Methods

Molecular analysis was carried out on the resistant isolates using a genome-wide characterisation approach, as well as MALDI-TOF mass spectrometry, to identify lipid A.

Results

Among the 32 carbapenem-resistant K. pneumoniae isolates, several isolates showed resistance and intermediate resistance to colistin. The seven isolates with intermediate resistance exhibited the “skip-well” phenomenon, attributed to the presence of resistant subpopulations. The three isolates with full resistance to colistin showed ions using MALDI-TOF mass spectrometry at m/z of 1840 and 1824 representing bisphosphorylated and hexa-acylated lipid A, respectively, with or without hydroxylation at position C’-2 of the fatty acyl chain. Studying the genetic environment of mgrB locus revealed the presence of two insertion sequences that disrupted the mgrB locus in the three colistin-resistant isolates: IS1R and IS903B.

Conclusions

Our findings show that colistin resistance/heteroresistance was inducible with mutations in chromosomal regulatory networks controlling the lipid A moiety and insertion sequences disrupting the mgrB gene, leading to elevated minimum inhibitory concentration values and treatment failure. Different treatment strategies should be employed to avoid colistin heteroresistance-linked treatment failures, mainly through combination therapy using colistin with carbapenems, aminoglycosides, or tigecycline.

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来源期刊
Journal of global antimicrobial resistance
Journal of global antimicrobial resistance INFECTIOUS DISEASES-PHARMACOLOGY & PHARMACY
CiteScore
8.70
自引率
2.20%
发文量
285
审稿时长
34 weeks
期刊介绍: The Journal of Global Antimicrobial Resistance (JGAR) is a quarterly online journal run by an international Editorial Board that focuses on the global spread of antibiotic-resistant microbes. JGAR is a dedicated journal for all professionals working in research, health care, the environment and animal infection control, aiming to track the resistance threat worldwide and provides a single voice devoted to antimicrobial resistance (AMR). Featuring peer-reviewed and up to date research articles, reviews, short notes and hot topics JGAR covers the key topics related to antibacterial, antiviral, antifungal and antiparasitic resistance.
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