title: Antibiotic failure mediated by a resistant subpopulation in Enterobacter cloacae.
abstract: Antibiotic resistance is a major public health threat, further complicated by unexplained treatment failures caused by bacteria that appear antibiotic susceptible. We describe an Enterobacter cloacae isolate harbouring a minor subpopulation that is highly resistant to the last-line antibiotic colistin. This subpopulation was distinct from persisters, became predominant in colistin, returned to baseline after colistin removal and was dependent on the histidine kinase PhoQ. During murine infection, but in the absence of colistin, innate immune defences led to an increased frequency of the resistant subpopulation, leading to inefficacy of subsequent colistin therapy. An isolate with a lower-frequency colistin-resistant subpopulation similarly caused treatment failure but was misclassified as susceptible by current diagnostics once cultured outside the host. These data demonstrate the ability of low-frequency bacterial subpopulations to contribute to clinically relevant antibiotic resistance, elucidating an enigmatic cause of antibiotic treatment failure and highlighting the critical need for more sensitive diagnostics.
authors: Department of Microbiology and Immunology, Emory University, Atlanta, Georgia 30329, USA.|Emory Vaccine Center, Atlanta, Georgia 30329, USA.
authors: Victor I
authors: VI
authors: Band
authors: Department of Microbiology and Immunology, Emory University, Atlanta, Georgia 30329, USA.|Emory Vaccine Center, Atlanta, Georgia 30329, USA.
authors: Emily K
authors: EK
authors: Crispell
authors: Department of Microbiology and Immunology, Emory University, Atlanta, Georgia 30329, USA.|Emory Vaccine Center, Atlanta, Georgia 30329, USA.
authors: Brooke A
authors: BA
authors: Napier
authors: Department of Infectious Disease, College of Veterinary Medicine, University of Georgia, Athens, Georgia 30602 USA.
authors: Carmen M
authors: CM
authors: Herrera
authors: Non-Human Primate Genomics Core, Yerkes National Primate Research Center, Robert W. Woodruff Health Sciences Center, Emory University, Atlanta, Georgia 30322, USA.
authors: Greg K
authors: GK
authors: Tharp
authors: Division of Infectious Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
authors: Kranthi
authors: K
authors: Vavikolanu
authors: Biotechnology Core Facility Branch, Centers for Disease Control, Atlanta, Georgia 30333, USA.
authors: Jan
authors: J
authors: Pohl
authors: Division of Infectious Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia 30322, USA.|Emory Antibiotic Resistance Center, Atlanta, Georgia 30329, USA.|Department of Human Genetics, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
authors: Timothy D
authors: TD
authors: Read
authors: Department of Microbiology and Immunology, Emory University, Atlanta, Georgia 30329, USA.|Emory Vaccine Center, Atlanta, Georgia 30329, USA.|Non-Human Primate Genomics Core, Yerkes National Primate Research Center, Robert W. Woodruff Health Sciences Center, Emory University, Atlanta, Georgia 30322, USA.
authors: Steven E
authors: SE
authors: Bosinger
authors: Department of Infectious Disease, College of Veterinary Medicine, University of Georgia, Athens, Georgia 30602 USA.
authors: M Stephen
authors: MS
authors: Trent
authors: Division of Infectious Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia 30322, USA.|Emory Antibiotic Resistance Center, Atlanta, Georgia 30329, USA.|Department of Pathology and Laboratory Medicine, Emory University, Atlanta, Georgia 30322, USA.
authors: Eileen M
authors: EM
authors: Burd
authors: Emory Vaccine Center, Atlanta, Georgia 30329, USA.|Division of Infectious Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia 30322, USA.|Emory Antibiotic Resistance Center, Atlanta, Georgia 30329, USA.|Research Service, Atlanta VA Medical Center, Decatur, Georgia 30033, USA.
authors: David S
authors: DS
authors: Weiss
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D001426:Bacterial Proteins / Q000378:metabolism; D003091:Colistin / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D024901:Drug Resistance, Multiple, Bacterial; D016972:Enterobacter cloacae / Q000187:drug effects* / Q000254:growth & development / Q000302:isolation & purification; D004756:Enterobacteriaceae Infections / Q000175:diagnosis / Q000188:drug therapy* / Q000276:immunology / Q000382:microbiology*; D000071677:Histidine Kinase / Q000378:metabolism; D007113:Immunity, Innate; D051379:Mice; D017211:Treatment Failure
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; C079792:PhoQ protein, Bacteria; D000071677:Histidine Kinase; D003091:Colistin