Cooperative action of SP-A and its trimeric recombinant fragment with polymyxins against Gram-negative respiratory bacteria.
Cooperative action of SP-A and its trimeric recombinant fragment with polymyxins against Gram-negative respiratory bacteria.
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DOI：
10.3389/fimmu.2022.927017
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发表时间：
2022
影响因子：
7.3
通讯作者：
中科院分区：
文献类型：
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作者：
由于多重耐药细菌问题日益严重，探索将抗微生物肺蛋白和常规抗生素相结合的治疗方法非常重要。本研究的目的是研究人SP-A和重组三聚体片段（rfhSP-A）是否与抗生素对致病性革兰氏阴性菌具有协同抗菌活性。我们发现SP-A与阳离子肽多粘菌素B（PMB）结合的表观解离常数（KD）为0.32 ± 0.04 µM。SP-A与多粘菌素B和E对三种SP-A耐药致病菌（肺炎克雷伯菌、非典型流感嗜血杆菌（NTHi）和铜绿假单胞菌）显示出协同杀微生物活性，但与其他抗生素无协同杀微生物活性。SP-A不能与K.肺炎链球菌、NTHi或其表达长链脂多糖（或脂寡糖）和/或多糖胶囊的突变株。在PMB存在下，SP-A诱导SP-A/PMB聚集体的形成，其增强PMB诱导的细菌膜透化。此外，SP-A还与PMB的无酰基链衍生物（PMBN）结合，形成SP-A/PMBN聚集体，其KD为0.26 ± 0.02 μM。PMBN不具有杀菌活性，但可与革兰氏阴性菌的外膜结合。令人惊讶的是，SP-A和PMBN显示出对革兰氏阴性菌的协同杀菌活性。与天然三聚体上SP-A不同，三聚体rfhSP-A片段对K.肺炎杆菌、NTHi和铜绿假单胞菌。rfhSP-A在生理条件下不与PMB结合，但与PMB和其他抗生素对这些病原菌起相加作用。总之，我们的研究结果显着提高了我们的了解SP-A的抗菌作用及其与PMB的协同作用。基于SP-A的肽可以帮助PMB的治疗用途，PMB是一种相对细胞毒性的抗生素，由于抗生素耐药性的全球性问题，目前正在重新引入临床。
The exploration of therapies combining antimicrobial lung proteins and conventional antibiotics is important due to the growing problem of multidrug-resistant bacteria. The aim of this study was to investigate whether human SP-A and a recombinant trimeric fragment (rfhSP-A) have cooperative antimicrobial activity with antibiotics against pathogenic Gram-negative bacteria. We found that SP-A bound the cationic peptide polymyxin B (PMB) with an apparent dissociation constant (K D) of 0.32 ± 0.04 µM. SP-A showed synergistic microbicidal activity with polymyxin B and E, but not with other antibiotics, against three SP-A-resistant pathogenic bacteria: Klebsiella pneumoniae, non-typable Haemophilus influenzae (NTHi), and Pseudomonas aeruginosa. SP-A was not able to bind to K. pneumoniae, NTHi, or to mutant strains thereof expressing long-chain lipopolysaccharides (or lipooligosaccharides) and/or polysaccharide capsules. In the presence of PMB, SP-A induced the formation of SP-A/PMB aggregates that enhance PMB-induced bacterial membrane permeabilization. Furthermore, SP-A bound to a molecular derivative of PMB lacking the acyl chain (PMBN) with a K D of 0.26 ± 0.02 μM, forming SP-A/PMBN aggregates. PMBN has no bactericidal activity but can bind to the outer membrane of Gram-negative bacteria. Surprisingly, SP-A and PMBN showed synergistic bactericidal activity against Gram-negative bacteria. Unlike native supratrimeric SP-A, the trimeric rfhSP-A fragment had small but significant direct bactericidal activity against K. pneumoniae, NTHi, and P. aeruginosa. rfhSP-A did not bind to PMB under physiological conditions but acted additively with PMB and other antibiotics against these pathogenic bacteria. In summary, our results significantly improve our understanding of the antimicrobial actions of SP-A and its synergistic action with PMB. A peptide based on SP-A may aid the therapeutic use of PMB, a relatively cytotoxic antibiotic that is currently being reintroduced into clinics due to the global problem of antibiotic resistance.
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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：
3.4
作者：
Canadas, Olga;Keough, Kevin M. W.;Casals, Cristina
通讯作者：
Casals, Cristina
影响因子：
3.4
作者：
Canadas, Olga;Garcia-Verdugo, Ignacio;Casals, Cristina
通讯作者：
Casals, Cristina
影响因子：
4.1
作者：
García-Verdugo, I;Sánchez-Barbero, F;Casals, S
通讯作者：
Casals, S
影响因子：
2.9
作者：
Domingues, Marco M.;Inacio, Rita G.;Santos, Nuno C.
通讯作者：
Santos, Nuno C.