title: Sheltering effect and indirect pathogenesis of carbapenem-resistant Acinetobacter baumannii in polymicrobial infection.
abstract: The role of carbapenem-resistant Acinetobacter baumannii (CRAb) in polymicrobial infection remains elusive. Having observed the ability of CRAb to shelter other susceptible bacteria from carbapenem killing, we sought to determine the factors contributing to this sheltering effect by transforming different recombinant plasmids into recipient A. baumannii cells. The sheltering effects of CRAb were reproduced in recipient A. baumannii cells that highly expressed carbapenem-hydrolyzing class D β-lactamases (CHDLs) through their associated strong promoter. With the use of Western blot analysis and a bioassay, the highly expressed CHDLs were found to be extracellularly released and led to hydrolysis of carbapenem. The level of extracellular CHDLs increased after challenge with a higher concentration of CHDL substrates, such as carbapenem and ticarcillin. This increased CHDL may, in part, be attributed to cell lysis, as indicated by the presence of extracellular gyrase. In the planktonic condition, the sheltering effect for the cocultured susceptible bacteria might represent an indirect and passive effect of the CRAb self-defense mechanism, because coculture with the susceptible pathogen did not augment the amount of the extracellular CHDLs. Polymicrobial infection caused by CRAb and a susceptible counterpart exerted higher pathogenicity than monomicrobial infection caused by either pathogen alone in mice receiving carbapenem therapy. This study demonstrated that CHDL-producing CRAb appears to provide a sheltering effect for carbapenem-susceptible pathogens via the extracellular release of CHDLs and, by this mechanism, can enhance the pathogenesis of polymicrobial infection in the presence of carbapenem therapy.
authors.affiliation: Institute of Clinical Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Yu-Ting
authors.initials: YT
authors.lastname: Liao
authors.affiliation: Institute of Clinical Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan National Institute of Infectious Diseases and Vaccinology, National Health Research Institutes, Zhunan, Miaoli County, Taiwan.
authors.forename: Shu-Chen
authors.initials: SC
authors.lastname: Kuo
authors.affiliation: Institute of Clinical Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan Department of Emergency Department, Taipei Veterans General Hospital, Taipei, Taiwan.
authors.forename: Yi-Tzu
authors.initials: YT
authors.lastname: Lee
authors.affiliation: Division of Infectious Diseases, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan.
authors.forename: Chien-Pei
authors.initials: CP
authors.lastname: Chen
authors.affiliation: Graduate Institute of Clinical Pharmacy, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors.forename: Shu-Wen
authors.initials: SW
authors.lastname: Lin
authors.affiliation: Graduate Institute of Clinical Pharmacy, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors.forename: Li-Jiuan
authors.initials: LJ
authors.lastname: Shen
authors.affiliation: Division of Infectious Diseases, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan Institute of Emergency and Critical Care Medicine, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Chang-Phone
authors.initials: CP
authors.lastname: Fung
authors.affiliation: Institute of Clinical Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan Department of Medicine, Mackay Medical College, Taipei, Taiwan wenlong.ym@gmail.com tecklayyy@gmail.com.
authors.forename: Wen-Long
authors.initials: WL
authors.lastname: Cho
authors.affiliation: Institute of Clinical Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan Division of Infectious Diseases, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan wenlong.ym@gmail.com tecklayyy@gmail.com.
authors.forename: Te-Li
authors.initials: TL
authors.lastname: Chen
mesh_terms: D000151:Acinetobacter Infections / Q000188:drug therapy / Q000382:microbiology*; D040981:Acinetobacter baumannii / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics*; D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology / Q000627:therapeutic use; D000907:Antibodies, Bacterial / Q000032:analysis / Q000096:biosynthesis; D001424:Bacterial Infections / Q000382:microbiology* / Q000473:pathology; D018920:Coculture Techniques; D015169:Colony Count, Microbial; D024881:Drug Resistance, Bacterial; D051379:Mice; D008810:Mice, Inbred C57BL; D008826:Microbial Sensitivity Tests; D010957:Plasmids; D018410:Pneumonia, Bacterial / Q000188:drug therapy / Q000382:microbiology; D001618:beta-Lactamases / Q000378:metabolism
chemical_list: D000900:Anti-Bacterial Agents; D000907:Antibodies, Bacterial; D001618:beta-Lactamases; C534889:beta-lactamase OXA-58, Acinetobacter baumannii