title: Fitness cost of antibiotic susceptibility during bacterial infection.
abstract: Advances in high-throughput DNA sequencing allow for a comprehensive analysis of bacterial genes that contribute to virulence in a specific infectious setting. Such information can yield new insights that affect decisions on how to best manage major public health issues such as the threat posed by increasing antimicrobial drug resistance. Much of the focus has been on the consequences of the selective advantage conferred on drug-resistant strains during antibiotic therapy. It is thought that the genetic and phenotypic changes that confer resistance also result in concomitant reductions in in vivo fitness, virulence, and transmission. However, experimental validation of this accepted paradigm is modest. Using a saturated transposon library of Pseudomonas aeruginosa, we identified genes across many functional categories and operons that contributed to maximal in vivo fitness during lung infections in animal models. Genes that bestowed both intrinsic and acquired antibiotic resistance provided a positive in vivo fitness advantage to P. aeruginosa during infection. We confirmed these findings in the pathogenic bacteria Acinetobacter baumannii and Vibrio cholerae using murine and rabbit infection models, respectively. Our results show that efforts to confront the worldwide increase in antibiotic resistance might be exacerbated by fitness advantages that enhance virulence in drug-resistant microbes.
authors.affiliation: Division of Infectious Diseases, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA. INSERM, IAME, UMR 1137, F-75018 Paris, France. Université Paris Diderot, Sorbonne Paris Cité, F-75018 Paris, France.
authors.forename: Damien
authors.initials: D
authors.lastname: Roux
authors.affiliation: Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Olga
authors.initials: O
authors.lastname: Danilchanka
authors.affiliation: Division of Infectious Diseases, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA. EA 4687, Faculté de Médecine, Université de Reims Champagne-Ardenne, 51092 Reims, France.
authors.forename: Thomas
authors.initials: T
authors.lastname: Guillard
authors.affiliation: Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115, USA. EA 4655, Faculté de Médecine, Université de Caen Basse-Normandie, 14033 Caen, France.
authors.forename: Vincent
authors.initials: V
authors.lastname: Cattoir
authors.affiliation: Department of Epidemiology, Harvard School of Public Health, Boston, MA 02115, USA.
authors.forename: Hugues
authors.initials: H
authors.lastname: Aschard
authors.affiliation: Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Yang
authors.initials: Y
authors.lastname: Fu
authors.affiliation: Hôpitaux de Paris (AP-HP), Pédiatrique Emergency Département, Hôpital Necker-Enfants Malades and Université Paris Descartes, 75015 Paris, France.
authors.forename: Francois
authors.initials: F
authors.lastname: Angoulvant
authors.affiliation: INSERM, IAME, UMR 1137, F-75018 Paris, France.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Messika
authors.affiliation: INSERM, IAME, UMR 1137, F-75018 Paris, France.
authors.forename: Jean-Damien
authors.initials: JD
authors.lastname: Ricard
authors.affiliation: Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: John J
authors.initials: JJ
authors.lastname: Mekalanos
authors.affiliation: Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Stephen
authors.initials: S
authors.lastname: Lory
authors.affiliation: Division of Infectious Diseases, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA. gpier@bwh.harvard.edu dskurnik@rics.bwh.harvard.edu.
authors.forename: Gerald B
authors.initials: GB
authors.lastname: Pier
authors.affiliation: Division of Infectious Diseases, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA. gpier@bwh.harvard.edu dskurnik@rics.bwh.harvard.edu.
authors.forename: David
authors.initials: D
authors.lastname: Skurnik
mesh_terms: D040981:Acinetobacter baumannii / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology / Q000627:therapeutic use*; D001424:Bacterial Infections / Q000188:drug therapy* / Q000382:microbiology*; D015169:Colony Count, Microbial; D017281:Cost of Illness; D004251:DNA Transposable Elements / Q000235:genetics; D004195:Disease Models, Animal; D004352:Drug Resistance, Microbial / Q000235:genetics; D041981:Gastrointestinal Tract / Q000473:pathology; D005798:Genes, Bacterial; D008168:Lung / Q000382:microbiology; D051379:Mice; D008826:Microbial Sensitivity Tests; D016254:Mutagenesis, Insertional / Q000235:genetics; D009154:Mutation / Q000235:genetics; D009876:Operon / Q000235:genetics; D011014:Pneumonia / Q000188:drug therapy / Q000382:microbiology; D011550:Pseudomonas aeruginosa / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D011817:Rabbits; D017422:Sequence Analysis, DNA; D014734:Vibrio cholerae / Q000187:drug effects / Q000235:genetics / Q000502:physiology
chemical_list: D000900:Anti-Bacterial Agents; D004251:DNA Transposable Elements