对产碳青霉烯酶肠杆菌科细菌具有保护作用的广谱抗体。
Extended-spectrum antibodies protective against carbapenemase-producing Enterobacteriaceae.
作者信息
Skurnik David, Roux Damien, Pons Stephanie, Guillard Thomas, Lu Xi, Cywes-Bentley Colette, Pier Gerald B
机构信息
Division of Infectious Diseases, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Division of Infectious Diseases, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
出版信息
J Antimicrob Chemother. 2016 Apr;71(4):927-35. doi: 10.1093/jac/dkv448. Epub 2016 Jan 7.
BACKGROUND
Carbapenem-resistant Enterobacteriaceae (CRE) are responsible for worldwide outbreaks and antibiotic treatments are problematic. The polysaccharide poly-(β-1,6)-N-acetyl glucosamine (PNAG) is a vaccine target detected on the surface of numerous pathogenic bacteria, including Escherichia coli. Genes encoding PNAG biosynthetic proteins have been identified in two other main pathogenic Enterobacteriaceae, Enterobacter cloacae and Klebsiella pneumoniae. We hypothesized that antibodies to PNAG might be a new therapeutic option for the different pan-resistant pathogenic species of CRE.
METHODS
PNAG production was detected by confocal microscopy and its role in the formation of the biofilm (for E. cloacae) and as a virulence factor (for K. pneumoniae) was analysed. The in vitro (opsonophagocytosis killing assay) and in vivo (mouse models of peritonitis) activity of antibodies to PNAG were studied using antibiotic-susceptible and -resistant E. coli, E. cloacae and K. pneumoniae. A PNAG-producing strain of Pseudomonas aeruginosa, an organism that does not naturally produce this antigen, was constructed by adding the pga locus to a strain with inactive alg genes responsible for the production of P. aeruginosa alginate. Antibodies to PNAG were tested in vitro and in vivo as above.
RESULTS
PNAG is a major component of the E. cloacae biofilm and a virulence factor for K. pneumoniae. Antibodies to PNAG mediated in vitro killing (>50%) and significantly protected mice against the New Delhi metallo-β-lactamase-producing E. coli (P = 0.02), E. cloacae (P = 0.0196) and K. pneumoniae (P = 0.006), against K. pneumoniae carbapenemase (KPC)-producing K. pneumoniae (P = 0.02) and against PNAG-producing P. aeruginosa (P = 0.0013). Thus, regardless of the Gram-negative bacterial species, PNAG expression is the sole determinant of the protective efficacy of antibodies to this antigen.
CONCLUSIONS
Our findings suggest antibodies to PNAG may provide extended-spectrum antibacterial protective activity.
背景
耐碳青霉烯类肠杆菌科细菌（CRE）在全球范围内引发疫情，抗生素治疗存在问题。多糖聚（β-1,6）-N-乙酰葡糖胺（PNAG）是在包括大肠杆菌在内的众多病原菌表面检测到的一种疫苗靶点。在另外两种主要致病性肠杆菌科细菌阴沟肠杆菌和肺炎克雷伯菌中已鉴定出编码PNAG生物合成蛋白的基因。我们推测，针对PNAG的抗体可能是治疗不同泛耐药性CRE致病菌种的一种新的治疗选择。
方法
通过共聚焦显微镜检测PNAG的产生，并分析其在生物膜形成（针对阴沟肠杆菌）和作为毒力因子（针对肺炎克雷伯菌）中的作用。使用对抗生素敏感和耐药的大肠杆菌、阴沟肠杆菌和肺炎克雷伯菌研究了针对PNAG的抗体的体外（调理吞噬杀伤试验）和体内（腹膜炎小鼠模型）活性。通过将pga基因座添加到负责铜绿假单胞菌藻酸盐产生的alg基因失活的菌株中，构建了一株产生PNAG的铜绿假单胞菌菌株，该菌株天然不产生这种抗原。如上述对针对PNAG的抗体进行体外和体内测试。
结果
PNAG是阴沟肠杆菌生物膜的主要成分和肺炎克雷伯菌的毒力因子。针对PNAG的抗体介导体外杀伤（>50%），并显著保护小鼠免受产新德里金属β-内酰胺酶的大肠杆菌（P = 0.02）、阴沟肠杆菌（P = 0.0196）和肺炎克雷伯菌（P = 0.006）、产肺炎克雷伯菌碳青霉烯酶（KPC）的肺炎克雷伯菌（P = 0.02）以及产PNAG的铜绿假单胞菌（P = 0.0013）的侵害。因此，无论革兰氏阴性菌的种类如何，PNAG的表达是针对该抗原的抗体保护效力的唯一决定因素。
结论
我们的研究结果表明，针对PNAG的抗体可能提供广谱抗菌保护活性。
Zotero 插件