Pseudomonas aeruginosa utilizes the host-derived polyamine spermidine to facilitate antimicrobial tolerance.
Pseudomonas aeruginosa utilizes the host-derived polyamine spermidine to facilitate antimicrobial tolerance.
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DOI：
10.1172/jci.insight.158879
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发表时间：
2022-11-22
期刊：
影响因子：
8
通讯作者：
Fothergill, Joanne L.
中科院分区：
文献类型：
--
作者：
Hasan, Chowdhury M.;Pottenger, Sian;Green, Angharad E.;Cox, Adrienne A.;White, Jack S.;Jones, Trevor;Winstanley, Craig;Kadioglu, Aras;Wright, Megan H.;Neill, Daniel R.;Fothergill, Joanne L.
铜绿假单胞菌在囊性纤维化 (CF) 肺感染期间经历多样化。了解这些变化需要能够捕捉 CF 肺部环境复杂性的模型系统。我们之前在 CF 肺部感染和小鼠实验性感染的铜绿假单胞菌中发现了 2 组分调节系统传感器激酶基因 pmrB 的功能丧失突变。在这里，我们证明，虽然此类突变降低了多种抗菌药物的体外最低抑制浓度，但这并没有反映在体内抗生素敏感性增加上。 PmrB 的缺失会损害 LPS 的氨基阿拉伯糖修饰，增加外膜的负电荷并促进阳离子抗菌剂的吸收。然而，在体内，这可以通过肺中其他带正电分子的膜结合增加来抵消。聚胺亚精胺很容易覆盖在缺乏 PmrB 的铜绿假单胞菌表面，降低了对依赖电荷差异结合外膜的抗生素的敏感性，并增加了生物膜的形成。在小鼠铜绿假单胞菌感染期间和 CF 患者接受抗菌治疗期间，肺部的亚精胺含量升高。这些发现强调了在临床相关环境条件下研究抗菌素耐药性的必要性。在体外携带适应性成本的微生物突变在感染期间可能是有利的，此时可以利用宿主资源。
Pseudomonas aeruginosa undergoes diversification during infection of the cystic fibrosis (CF) lung. Understanding these changes requires model systems that capture the complexity of the CF lung environment. We previously identified loss-of-function mutations in the 2-component regulatory system sensor kinase gene pmrB in P. aeruginosa from CF lung infections and from experimental infection of mice. Here, we demonstrate that, while such mutations lowered in vitro minimum inhibitory concentrations for multiple antimicrobial classes, this was not reflected in increased antibiotic susceptibility in vivo. Loss of PmrB impaired aminoarabinose modification of LPS, increasing the negative charge of the outer membrane and promoting uptake of cationic antimicrobials. However, in vivo, this could be offset by increased membrane binding of other positively charged molecules present in lungs. The polyamine spermidine readily coated the surface of PmrB-deficient P. aeruginosa, reducing susceptibility to antibiotics that rely on charge differences to bind the outer membrane and increasing biofilm formation. Spermidine was elevated in lungs during P. aeruginosa infection in mice and during episodes of antimicrobial treatment in people with CF. These findings highlight the need to study antimicrobial resistance under clinically relevant environmental conditions. Microbial mutations carrying fitness costs in vitro may be advantageous during infection, where host resources can be utilized.
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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：
4.9
作者：
Kwon, Dong-Hyeon;Lu, Chung-Dar
通讯作者：
Lu, Chung-Dar
影响因子：
6.4
作者：
Ernst, Robert K.;Moskowitz, Samuel M.;Miller, Samuel I.
通讯作者：
Miller, Samuel I.
影响因子：
3.2
作者：
McPhee, Joseph B.;Bains, Manjeet;Hancock, R. E. W.
通讯作者：
Hancock, R. E. W.
影响因子：
3.9
作者：
Moore MP;Lamont IL;Williams D;Paterson S;Kukavica-Ibrulj I;Tucker NP;Kenna DTD;Turton JF;Jeukens J;Freschi L;Wee BA;Loman NJ;Holden S;Manzoor S;Hawkey P;Southern KW;Walshaw MJ;Levesque RC;Fothergill JL;Winstanley C
通讯作者：
Winstanley C