Widespread emergence of OmpK36 loop 3 insertions among multidrug-resistant clones of Klebsiella pneumoniae
Widespread emergence of OmpK36 loop 3 insertions among multidrug-resistant clones of Klebsiella pneumoniae
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肺炎克雷伯菌多重耐药克隆中广泛出现 OmpK36 环 3 插入
DOI：
10.1101/2022.02.07.479342
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发表时间：
2022
期刊：
影响因子：
--
通讯作者：
David S
中科院分区：
文献类型：
--
作者：
David S
外膜孔蛋白的突变与碳青霉烯酶协同作用，增加重要的医院病原体肺炎克雷伯菌（KP）对碳青霉烯的耐药性。一个关键的例子是在OmpK 36的细胞外环3（L3）区域中的二氨基酸插入，甘氨酸-天冬氨酸（GD），其收缩孔并限制碳青霉烯类进入细菌细胞。在这里，我们结合了基因组和实验方法来研究OmpK 36中不同L3插入类型的多样性，传播和影响。我们在来自全球收集的14，888个KP基因组中的3588个（24.1%）中鉴定了L3插入，其中包含完整的pK 36基因。GD插入是最常见的，在欧洲和美洲广泛传播的ST 258/512克隆中具有高浓度。天冬氨酸（D）和苏氨酸-天冬氨酸（TD）插入在亚洲基因组中普遍存在，部分原因是KP序列类型ST 16和ST 231的获得以及随后的克隆扩增。通过解析新型OmpK 36变体的晶体结构，我们发现TD插入导致41%的孔收缩，显著大于GD（10%）或D（8%）所实现的孔收缩，导致对所选抗生素的最高水平的抗性。我们表明，在没有抗生素的KP突变体窝藏这些L3插入表现出anin vitroandin vivo竞争相对于表达野生型OmpK 36的同基因亲本菌株的劣势。我们认为这解释了在KP基因组中观察到的低频率GD和TD插入的逆转。最后，我们证明了表达L3插入的菌株仍然对靶向产碳青霉烯酶的KP的药物敏感，包括新型β内酰胺-β内酰胺酶抑制剂组合。这项研究提供了一个当代的全球视野OmpK 36介导的耐药机制在KP，整合监测和实验数据，以指导治疗和药物开发策略。
Mutations in outer membrane porins act in synergy with carbapenemase enzymes to increase carbapenem resistance in the important nosocomial pathogen,Klebsiella pneumoniae(KP). A key example is a di-amino acid insertion, Glycine-Aspartate (GD), in the extracellular loop 3 (L3) region of OmpK36 which constricts the pore and restricts entry of carbapenems into the bacterial cell. Here we combined genomic and experimental approaches to characterise the diversity, spread and impact of different L3 insertion types in OmpK36. We identified L3 insertions in 3588 (24.1%) of 14,888 KP genomes with an intactompK36gene from a global collection. GD insertions were most common, with a high concentration in the ST258/512 clone that has spread widely in Europe and the Americas. Aspartate (D) and Threonine-Aspartate (TD) insertions were prevalent in genomes from Asia, due in part to acquisitions by KP sequence types ST16 and ST231 and subsequent clonal expansions. By solving the crystal structures of novel OmpK36 variants, we found that the TD insertion causes a pore constriction of 41%, significantly greater than that achieved by GD (10%) or D (8%), resulting in the highest levels of resistance to selected antibiotics. We show that in the absence of antibiotics KP mutants harbouring these L3 insertions exhibit both anin vitroandin vivocompetitive disadvantage relative to the isogenic parental strain expressing wild type OmpK36. We propose that this explains the reversion of GD and TD insertions observed at low frequency among KP genomes. Finally, we demonstrate that strains expressing L3 insertions remain susceptible to drugs targeting carbapenemase-producing KP, including novel beta lactam-beta lactamase inhibitor combinations. This study provides a contemporary global view of OmpK36-mediated resistance mechanisms in KP, integrating surveillance and experimental data to guide treatment and drug development strategies.
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影响因子：
16.6
作者：
Lam MMC;Wick RR;Watts SC;Cerdeira LT;Wyres KL;Holt KE
通讯作者：
Holt KE
缺乏碳青霉烯酶的厄他培南非敏感分离株中肺炎克雷伯菌主要孔蛋白的全球调查
影响因子：
3
作者：
M. Wise;E. Horvath;K. Young;D. Sahm;K. Kazmierczak
通讯作者：
K. Kazmierczak
DOI：
10.1101/2021.06.22.448967
发表时间：
2021-06
期刊：
Clinical Infectious Diseases: An Official Publication of the Infectious Diseases Society of America
影响因子：
--
作者：
S. Argimón;S. David;A. Underwood;M. Abrudan;N. Wheeler;M. Kekre;Khalil AbuDahab;C. Yeats;Richard J. Goater;Ben Taylor;Harry Harste;Dawn Muddyman;E. Feil;S. Brisse;K. Holt;P. Donado-Godoy;K. Ravikumar;I. Okeke;C. Carlos;D. Aanensen
通讯作者：
S. Argimón;S. David;A. Underwood;M. Abrudan;N. Wheeler;M. Kekre;Khalil AbuDahab;C. Yeats;Richard J. Goater;Ben Taylor;Harry Harste;Dawn Muddyman;E. Feil;S. Brisse;K. Holt;P. Donado-Godoy;K. Ravikumar;I. Okeke;C. Carlos;D. Aanensen
影响因子：
3.9
作者：
Argimón S;Abudahab K;Goater RJE;Fedosejev A;Bhai J;Glasner C;Feil EJ;Holden MTG;Yeats CA;Grundmann H;Spratt BG;Aanensen DM
通讯作者：
Aanensen DM
酪蛋白酸水解物替代蛋白胨制备细菌培养基
影响因子：
4.4
作者：
J. Mueller;E. R. Johnson
通讯作者：
E. R. Johnson