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影响外膜脂质不对称系统(MlaA-OmpC/F)的肽可减少禽致病性大肠杆菌(APEC)在鸡中的定植。

Peptides Affecting the Outer Membrane Lipid Asymmetry System (MlaA-OmpC/F) Reduce Avian Pathogenic Escherichia coli (APEC) Colonization in Chickens.

机构信息

Center for Food Animal Health, Department of Animal Sciences, The Ohio State University, Wooster, Ohio, USA.

出版信息

Appl Environ Microbiol. 2021 Aug 11;87(17):e0056721. doi: 10.1128/AEM.00567-21.

Abstract

Avian pathogenic Escherichia coli (APEC), an extraintestinal pathogenic E. coli (ExPEC), causes colibacillosis in chickens and is reportedly associated with urinary tract infections and meningitis in humans. Development of resistance is a major limitation of current ExPEC antibiotic therapy. New antibacterials that can circumvent resistance problem such as antimicrobial peptides (AMPs) are critically needed. Here, we evaluated the efficacy of Lactobacillus rhamnosus GG (LGG)-derived peptides against APEC and uncovered their potential antibacterial targets. Three peptides (NPSRQERR [P1], PDENK [P2], and VHTAPK [P3]) displayed inhibitory activity against APEC. These peptides were effective against APEC in biofilm and chicken macrophage HD11 cells. Treatment with these peptides reduced the cecum colonization (0.5 to 1.3 log) of APEC in chickens. Microbiota analysis revealed two peptides (P1 and P2) decreased abundance with minimal impact on overall cecal microbiota of chickens. Bacterial cytological profiling showed peptides disrupt APEC membranes either by causing membrane shedding, rupturing, or flaccidity. Furthermore, gene expression analysis revealed that peptides downregulated the expression of (>13.0-fold), (>11.3-fold), and (>4.9-fold), genes responsible for the maintenance of outer membrane (OM) lipid asymmetry. Consistently, immunoblot analysis also showed decreased levels of OmpC and MlaA proteins in APEC treated with peptides. Alanine scanning studies revealed residues crucial (P1, N, E, R and P; P2, D and E; P3, T, P, and K) for their activity. Overall, our study identified peptides with a new antibacterial target that can be developed to control APEC infections in chickens, thereby curtailing poultry-originated human ExPEC infections. Avian pathogenic Escherichia coli (APEC) is a subgroup of extraintestinal pathogenic E. coli (ExPEC) and considered a foodborne zoonotic pathogen transmitted through consumption of contaminated poultry products. APEC shares genetic similarities with human ExPECs, including uropathogenic E. coli (UPEC) and neonatal meningitis E. coli (NMEC). Our study identified Lactobacillus rhamnosus GG (LGG)-derived peptides (P1 [NPSRQERR], P2 [PDENK], and P3 [VHTAPK]) effective in reducing APEC infection in chickens. Antimicrobial peptides (AMPs) are regarded as ideal candidates for antibacterial development because of their low propensity for resistance development and ability to kill resistant bacteria. Mechanistic studies showed peptides disrupt the APEC membrane by affecting the MlaA-OmpC/F system responsible for the maintenance of outer membrane (OM) lipid asymmetry, a promising new druggable target to overcome resistance problems in Gram-negative bacteria. Altogether, these peptides can provide a valuable approach for development of novel anti-ExPEC therapies, including APEC, human ExPECs, and other related Gram-negative pathogens. Furthermore, effective control of APEC infections in chickens can curb poultry-originated ExPEC infections in humans.

摘要

禽致病性大肠杆菌(APEC)是一种肠外致病性大肠杆菌(ExPEC),可引起鸡的大肠杆菌病,并据报道与人类的尿路感染和脑膜炎有关。目前 ExPEC 抗生素治疗的主要局限性是耐药性的发展。非常需要能够规避耐药性问题的新型抗菌药物,例如抗菌肽(AMPs)。在这里,我们评估了鼠李糖乳杆菌 GG(LGG)衍生肽对 APEC 的功效,并揭示了它们的潜在抗菌靶标。三种肽(NPSRQERR [P1]、PDENK [P2]和 VHTAPK [P3])对 APEC 表现出抑制活性。这些肽在生物膜和鸡巨噬细胞 HD11 细胞中对 APEC 有效。用这些肽处理可减少 APEC 在鸡盲肠中的定植(减少 0.5 至 1.3 个对数)。微生物组分析显示,两种肽(P1 和 P2)减少了鸡盲肠微生物组的丰度,对其整体影响最小。细菌细胞学分析表明,这些肽通过引起膜脱落、破裂或松弛来破坏 APEC 膜。此外,基因表达分析显示,肽下调了维持外膜(OM)脂质不对称性的基因(>13.0 倍)、(>11.3 倍)和(>4.9 倍)的表达。一致地,免疫印迹分析还显示用肽处理的 APEC 中 OmpC 和 MlaA 蛋白水平降低。丙氨酸扫描研究表明,这些肽的活性关键残基(P1,N、E、R 和 P;P2,D 和 E;P3,T、P 和 K)。总体而言,我们的研究确定了具有新抗菌靶标的肽,可用于开发控制鸡 APEC 感染的方法,从而减少禽源人 ExPEC 感染。禽致病性大肠杆菌(APEC)是肠外致病性大肠杆菌(ExPEC)的一个亚群,被认为是通过食用受污染的家禽产品传播的食源性病原体。APEC 与人类 ExPEC 具有遗传相似性,包括尿路致病性大肠杆菌(UPEC)和新生儿脑膜炎大肠杆菌(NMEC)。我们的研究确定了鼠李糖乳杆菌 GG(LGG)衍生的肽(P1 [NPSRQERR]、P2 [PDENK] 和 P3 [VHTAPK])可有效减少鸡的 APEC 感染。抗菌肽(AMPs)因其低耐药性倾向和杀死耐药菌的能力而被认为是理想的抗菌药物开发候选物。机制研究表明,肽通过影响维持外膜(OM)脂质不对称性的 MlaA-OmpC/F 系统来破坏 APEC 膜,这是一个有前途的新的可药物靶标,可克服革兰氏阴性菌的耐药性问题。总的来说,这些肽可以为开发新型抗 ExPEC 疗法提供有价值的方法,包括 APEC、人类 ExPEC 和其他相关的革兰氏阴性病原体。此外,有效控制鸡的 APEC 感染可以减少人类禽源 ExPEC 感染。

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