Determination of Mutational Timing of Colistin-Resistance Genes through Klebsiella pneumoniae Evolution.
Determination of Mutational Timing of Colistin-Resistance Genes through Klebsiella pneumoniae Evolution.
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DOI：
10.3390/pharmaceutics15010270
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发表时间：
2023-01-12
期刊：
影响因子：
5.4
通讯作者：
Di YP
中科院分区：
文献类型：
--
作者：
Kuhn JM;Di YP
耐碳青霉烯类肺炎克雷伯菌(KP)是耐碳青霉烯类肠杆菌科(CRE)中的一种，它的出现和传播是医院内耐药感染的一个新的原因，与高发病率和死亡率相关。粘菌素，或多粘菌素E，是一种最后的多肽抗生素，用于治疗包括KP在内的多药耐药(MDR)革兰氏阴性细菌感染。不幸的是，随着临床使用的增加，对粘菌素的耐药性正在上升。虽然临床证据表明某些突变与KP中的粘菌素耐药(COL-R)有关，但这些突变的起源和关联仍不清楚。我们假设COL-R突变的时机影响了KP对粘菌素耐药的发展和进展。我们进行了KP菌株ATCC 43816在增加粘菌素浓度下的浮游和生物膜体外实验进化，以表征关键的COL-R突变在COL-R过程中的时间调节。比较了具有不同生活方式的独立进化细菌种群的抗性世代和突变谱。具有不同功能的基因推测了关键突变产生的时间线及其在COL-R进展中的作用。我们的结果旨在推进有效疗法的研究和开发，以治疗耐多药细菌感染，因为CRE的传播仍然是一个严重的公共健康威胁。
The emergence and dissemination of carbapenem-resistant Klebsiella pneumoniae (KP), one of the carbapenem-resistant Enterobacteriaceae (CRE), is now an emerging cause of antibiotic-resistant nosocomial infections associated with high rates of morbidity and mortality. Colistin, or polymyxin E, is a last-resort peptide antibiotic used to treat multidrug-resistant (MDR) Gram-negative bacterial infections including KP. Unfortunately, resistance to colistin is rising with increasing use in the clinical setting. Although clinical evidence links certain mutations to colistin resistance (COL-R) in KP, the origination and association of the mutations remain unclear. We hypothesize that the timing of COL-R mutations influences the development and progression of KP resistance to colistin. We performed planktonic and biofilm in vitro experimental evolutions of KP strain ATCC 43816 under increasing colistin concentrations to characterize the temporal regulation of critical COL-R mutations throughout COL-R progression. The resistance generation and mutation profiles of independently evolved bacterial populations with different lifestyles were compared. Genes with various functions theorize the timeline in which key mutations are generated and their roles in the progression of COL-R. Our results aim to advance the research and development of effective therapeutics to treat MDR bacterial infection as the dissemination of CRE continues to be a severe public health threat.
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影响因子：
13.6
作者：
Ghilarov D;Inaba-Inoue S;Stepien P;Qu F;Michalczyk E;Pakosz Z;Nomura N;Ogasawara S;Walker GC;Rebuffat S;Iwata S;Heddle JG;Beis K
通讯作者：
Beis K
DOI：
10.1038/s41580-020-00313-x
发表时间：
2021-03
期刊：
Nature reviews. Molecular cell biology
影响因子：
--
作者：
Covarrubias AJ;Perrone R;Grozio A;Verdin E
通讯作者：
Verdin E
影响因子：
3.6
作者：
Gunn, JS;Lim, KB;Miller, SI
通讯作者：
Miller, SI
影响因子：
4
作者：
Ghosal, Anubrata;Vitali, Ally;Nielsen, Peter E.
通讯作者：
Nielsen, Peter E.
影响因子：
6.7
作者：
del Pozo, J. L.;Patel, R.
通讯作者：
Patel, R.