TAM mediates adaptation of carbapenem-resistant Klebsiella pneumoniae to antimicrobial stress during host colonization and infection.
TAM mediates adaptation of carbapenem-resistant Klebsiella pneumoniae to antimicrobial stress during host colonization and infection.
复制标题
DOI：
10.1371/journal.ppat.1009309
复制
发表时间：
2021-03
期刊：
影响因子：
6.7
通讯作者：
Pamer EG
中科院分区：
文献类型：
--
作者：
Jung HJ;Sorbara MT;Pamer EG
革兰氏阴性病原体，如肺炎克雷伯氏菌，重塑其外膜（OM），以应对压力，以保持其作为有效屏障的完整性，从而促进其在宿主中的生存。对碳青霉烯类抗生素耐药的克雷伯氏菌的出现，对几乎所有抗生素都有抗性的肺炎（CR-Kp）菌株是一个日益严重的临床问题，OM不渗透性限制了抗微生物剂的发展，因为更高分子量的抗生素不能进入活性位点。在这里，我们证明了TAM（易位和组装模块）缺失增加了CR-Kp OM渗透性的压力条件下，并提高了高分子量抗菌剂的敏感性。基于SILAC的蛋白质组学分析揭示了TAM缺陷株中膜蛋白的错误定位。应激诱导的致敏作用增强了TAM缺陷型CR-Kp在粪便微生物群移植后从肠腔和在肺部或全身感染后从感染部位的清除。我们的研究表明，TAM作为OM渗透性的调节剂，代表了开发增强现有抗生素有效性的药物的潜在目标。抗生素在控制细菌感染方面仍然非常有效，然而，部分由于它们在临床和农业环境中的广泛使用，许多微生物病原体已经产生了抗生素耐药性。开发新的抗微生物剂来治疗多重耐药感染对于革兰氏阴性菌如肺炎克雷伯菌（Klebsiella pneumoniae）尤其具有挑战性，肺炎克雷伯菌是医院感染的主要原因。这些细菌在包膜中有一个额外的层，这阻止了潜在的临床有用的抗菌化合物进入活性部位。在这项研究中，我们证明了易位和组装模块（TAM）介导的抗生素和抗菌肽的耐药性在宿主定植和感染高耐药性K。肺炎克雷伯氏菌（CR-Kp）。TAM的损失损害了包膜生物合成，并增加了应激条件下CR-Kp对大抗微生物剂的敏感性。应激诱导的致敏增强了CR-Kp从肠腔以及感染部位的清除。我们的发现为治疗剂提供了一个潜在的靶点，以增强渗透性，从而提高现有和潜在抗生素的有效性。
Gram-negative pathogens, such as Klebsiella pneumoniae, remodel their outer membrane (OM) in response to stress to maintain its integrity as an effective barrier and thus to promote their survival in the host. The emergence of carbapenem-resistant K. pneumoniae (CR-Kp) strains that are resistant to virtually all antibiotics is an increasing clinical problem and OM impermeability has limited development of antimicrobial agents because higher molecular weight antibiotics cannot access sites of activity. Here, we demonstrate that TAM (translocation and assembly module) deletion increases CR-Kp OM permeability under stress conditions and enhances sensitivity to high-molecular weight antimicrobials. SILAC-based proteomic analyses revealed mis-localization of membrane proteins in the TAM deficient strain. Stress-induced sensitization enhances clearance of TAM-deficient CR-Kp from the gut lumen following fecal microbiota transplantation and from infection sites following pulmonary or systemic infection. Our study suggests that TAM, as a regulator of OM permeability, represents a potential target for development of agents that enhance the effectiveness of existing antibiotics. Antibiotics remain remarkably effective at controlling bacterial infections, however, in part due to their extensive use in clinical and agricultural settings, many microbial pathogens have developed antibiotic resistance. Development of new antimicrobial agents to treat multidrug-resistant infections is particularly challenging for Gram-negative bacteria such as Klebsiella pneumoniae, a leading cause of nosocomial infection. Those bacteria have an additional layer in the envelope, which prevents potentially clinically useful antimicrobial compounds to access sites of activity. In this study, we demonstrate that translocation and assembly module (TAM) mediates antibiotic and antimicrobial peptide resistance during host colonization and infection with highly antibiotic-resistant K. pneumoniae (CR-Kp). Loss of TAM impaired the envelope biogenesis and increased the sensitivity of CR-Kp to large antimicrobials under stress conditions. Stress-induced sensitization enhanced clearance of CR-Kp from the gut lumen as well as from infection sites. Our finding offers a potential target for therapeutic agents to enhance permeability and thus effectiveness of existing and potential antibiotics.
登录
查看更多内容
影响因子：
4.9
作者：
Hatfaludi, Tamas;Al-Hasani, Keith;Adler, Ben
通讯作者：
Adler, Ben
DOI：
10.1016/j.bbapap.2008.11.005
发表时间：
2009-05
期刊：
Biochimica et biophysica acta
影响因子：
--
作者：
Delcour AH
通讯作者：
Delcour AH
影响因子：
30.3
作者：
Dalebroux, Zachary D.;Edrozo, Mauna B.;Miller, Samuel I.
通讯作者：
Miller, Samuel I.
影响因子：
30.3
作者：
Caballero S;Kim S;Carter RA;Leiner IM;Sušac B;Miller L;Kim GJ;Ling L;Pamer EG
通讯作者：
Pamer EG
影响因子：
2.9
作者：
GOOD, NE;WINGET, GD;SINGH, RMM
通讯作者：
SINGH, RMM