Bactericidal monoclonal antibodies specific to the lipopolysaccharide O antigen from multidrug-resistant Escherichia coli clone ST131-O25b:H4 elicit protection in mice

• Published in: Antimicrobial agents and chemotherapy Vol. 59; no. 6; pp. 3109 - 3116
• Main Authors: Szijártó, Valéria, Guachalla, Luis M, Visram, Zehra C, Hartl, Katharina, Varga, Cecília, Mirkina, Irina, Zmajkovic, Jakub, Badarau, Adriana, Zauner, Gerhild, Pleban, Clara, Magyarics, Zoltán, Nagy, Eszter, Nagy, Gábor
• Format: Journal Article
• Language: English
• Published: United States American Society for Microbiology 01.06.2015
• Subjects: Animals; Anti-Bacterial Agents; Anti-Bacterial Agents - pharmacology; Anti-Bacterial Agents - therapeutic use; Antibodies, Monoclonal; Antibodies, Monoclonal - pharmacology; Antibodies, Monoclonal - therapeutic use; Drug Resistance, Multiple, Bacterial; Escherichia coli; Escherichia coli - drug effects; Escherichia coli - metabolism; Escherichia coli Infections - drug therapy; Escherichia coli Infections - microbiology; Experimental Therapeutics; Female; Mice; O Antigens; O Antigens - metabolism
• ISSN: 0066-4804; 1098-6596
• DOI: 10.1128/AAC.04494-14

The Escherichia coli sequence type 131 (ST131)-O25b:H4 clone has spread worldwide and become responsible for a significant proportion of multidrug-resistant extraintestinal infections. We generated humanized monoclonal antibodies (MAbs) that target the lipopolysaccharide O25b antigen conserved within this lineage. These MAbs bound to the surface of live bacterial cells irrespective of the capsular type expressed. In a serum bactericidal assay in vitro, MAbs induced >95% bacterial killing in the presence of human serum as the complement source. Protective efficacy at low antibody doses was observed in a murine model of bacteremia. The mode of action in vivo was investigated by using aglycosylated derivatives of the protective MAbs. The significant binding to live E. coli cells and the in vitro and in vivo efficacy were corroborated in assays using bacteria grown in human serum to mimic relevant clinical conditions. Given the dry pipeline of novel antibiotics against multidrug-resistant Gram-negative pathogens, passive immunization with bactericidal antibodies offers a therapeutic alternative to control infections caused by E. coli ST131-O25b:H4.