Colistin resistance mutations in phoQ can sensitize Klebsiella pneumoniae to IgM-mediated complement killing.
Colistin resistance mutations in phoQ can sensitize Klebsiella pneumoniae to IgM-mediated complement killing.
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DOI：
10.1038/s41598-023-39613-5
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发表时间：
2023-08-03
影响因子：
4.6
通讯作者：
Bardoel, Bart W.
中科院分区：
文献类型：
--
作者：
van der Lans, Sjors P. A.;Janet-Maitre, Manon;Masson, Frerich M.;Walker, Kimberly A.;Doorduijn, Dennis J.;Janssen, Axel B.;van Schaik, Willem;Attree, Ina;Rooijakkers, Suzan H. M.;Bardoel, Bart W.
由于多重耐药，医生越来越多地使用最后手段的抗生素粘菌素来治疗革兰氏阴性杆菌肺炎克雷伯菌感染。不幸的是，肺炎克雷伯菌也会对粘菌素产生抗药性。有趣的是，粘菌素耐药性对免疫系统清除细菌有双重影响。虽然粘菌素增加了对抗菌肽的耐药性，但据报道，粘菌素耐药性会使某些细菌变得敏感，从而被人血清杀死。在这里，我们研究了血清敏感性增加的机制，重点是人类补体通过膜攻击复合体(MAC)毛孔杀死革兰氏阴性菌。利用体外进化的粘菌素抗性菌株和荧光MAC介导的渗透试验，我们发现三个被测的粘菌素抗性菌株中的两个，Kp209_CSTR和Kp257_CSTR对MAC敏感。针对Kp209_CSTR的转录和机制分析表明，PhoQ基因中的一个突变将PhoQ锁定在激活状态，使Kp209_CSTR对粘菌素产生抗性，并对MAC敏感。详细的免疫学分析表明，补体激活Kp209_CSTR需要结合Kp209_CSTR的特异性IgM抗体，但不识别野生型毒株。综上所述，我们的结果表明，粘菌素耐药性的形成影响了Kp209_CSTR的识别和免疫系统对其的杀伤。
Due to multi-drug resistance, physicians increasingly use the last-resort antibiotic colistin to treat infections with the Gram-negative bacterium Klebsiella pneumoniae. Unfortunately, K. pneumoniae can also develop colistin resistance. Interestingly, colistin resistance has dual effects on bacterial clearance by the immune system. While it increases resistance to antimicrobial peptides, colistin resistance has been reported to sensitize certain bacteria for killing by human serum. Here we investigate the mechanisms underlying this increased serum sensitivity, focusing on human complement which kills Gram-negatives via membrane attack complex (MAC) pores. Using in vitro evolved colistin resistant strains and a fluorescent MAC-mediated permeabilization assay, we showed that two of the three tested colistin resistant strains, Kp209_CSTR and Kp257_CSTR, were sensitized to MAC. Transcriptomic and mechanistic analyses focusing on Kp209_CSTR revealed that a mutation in the phoQ gene locked PhoQ in an active state, making Kp209_CSTR colistin resistant and MAC sensitive. Detailed immunological assays showed that complement activation on Kp209_CSTR in human serum required specific IgM antibodies that bound Kp209_CSTR but did not recognize the wild-type strain. Together, our results show that developing colistin resistance affected recognition of Kp209_CSTR and its killing by the immune system.
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影响因子：
48
作者：
Langmead, Ben;Salzberg, Steven L.
通讯作者：
Salzberg, Steven L.
DOI：
10.1093/bioinformatics/btu638
发表时间：
2015-01-15
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Anders S;Pyl PT;Huber W
通讯作者：
Huber W
影响因子：
4.5
作者：
Andrade FF;Silva D;Rodrigues A;Pina-Vaz C
通讯作者：
Pina-Vaz C
影响因子：
5.2
作者：
Lepuschitz S;Hauser K;Schriebl A;Schlagenhaufen C;Stöger A;Chakeri A;Vötsch K;Pekard-Amenitsch S;Springer B;Allerberger F;Ruppitsch W
通讯作者：
Ruppitsch W
影响因子：
5.6
作者：
Chamnongpol, S;Cromie, M;Groisman, EA
通讯作者：
Groisman, EA