title: Small-plasmid-mediated antibiotic resistance is enhanced by increases in plasmid copy number and bacterial fitness.
abstract: Plasmids play a key role in the horizontal spread of antibiotic resistance determinants among bacterial pathogens. When an antibiotic resistance plasmid arrives in a new bacterial host, it produces a fitness cost, causing a competitive disadvantage for the plasmid-bearing bacterium in the absence of antibiotics. On the other hand, in the presence of antibiotics, the plasmid promotes the survival of the clone. The adaptations experienced by plasmid and bacterium in the presence of antibiotics during the first generations of coexistence will be crucial for the progress of the infection and the maintenance of plasmid-mediated resistance once the treatment is over. Here we developed a model system using the human pathogen Haemophilus influenzae carrying the small plasmid pB1000 conferring resistance to β-lactam antibiotics to investigate host and plasmid adaptations in the course of a simulated ampicillin therapy. Our results proved that plasmid-bearing clones compensated for the fitness disadvantage during the first 100 generations of plasmid-host adaptation. In addition, ampicillin treatment was associated with an increase in pB1000 copy number. The augmentation in both bacterial fitness and plasmid copy number gave rise to H. influenzae populations with higher ampicillin resistance levels. In conclusion, we show here that the modulations in bacterial fitness and plasmid copy number help a plasmid-bearing bacterium to adapt during antibiotic therapy, promoting both the survival of the host and the spread of the plasmid.
authors.affiliation: Departamento de Sanidad Animal and Centro de Vigilancia Sanitaria Veterinaria, Facultad de Veterinaria, Universidad Complutense de Madrid, Madrid, Spain bgzorn@ucm.es alvaro.sanmillan@zoo.ox.ac.uk.
authors.forename: Alvaro
authors.initials: A
authors.lastname: San Millan
authors.affiliation: Departamento de Sanidad Animal and Centro de Vigilancia Sanitaria Veterinaria, Facultad de Veterinaria, Universidad Complutense de Madrid, Madrid, Spain.
authors.forename: Alfonso
authors.initials: A
authors.lastname: Santos-Lopez
authors.affiliation: Departamento de Sanidad Animal and Centro de Vigilancia Sanitaria Veterinaria, Facultad de Veterinaria, Universidad Complutense de Madrid, Madrid, Spain.
authors.forename: Rafael
authors.initials: R
authors.lastname: Ortega-Huedo
authors.affiliation: Departamento de Sanidad Animal and Centro de Vigilancia Sanitaria Veterinaria, Facultad de Veterinaria, Universidad Complutense de Madrid, Madrid, Spain.
authors.forename: Cristina
authors.initials: C
authors.lastname: Bernabe-Balas
authors.affiliation: INRA, MetaGenoPolis US1367, Jouy en Josas, France.
authors.forename: Sean P
authors.initials: SP
authors.lastname: Kennedy
authors.affiliation: Departamento de Sanidad Animal and Centro de Vigilancia Sanitaria Veterinaria, Facultad de Veterinaria, Universidad Complutense de Madrid, Madrid, Spain bgzorn@ucm.es alvaro.sanmillan@zoo.ox.ac.uk.
authors.forename: Bruno
authors.initials: B
authors.lastname: Gonzalez-Zorn
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D056915:DNA Copy Number Variations / Q000235:genetics; D004352:Drug Resistance, Microbial / Q000235:genetics; D006193:Haemophilus influenzae / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D010957:Plasmids / Q000235:genetics*
chemical_list: D000900:Anti-Bacterial Agents
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