title: Pervasive sign epistasis between conjugative plasmids and drug-resistance chromosomal mutations.
abstract: Multidrug-resistant bacteria arise mostly by the accumulation of plasmids and chromosomal mutations. Typically, these resistant determinants are costly to the bacterial cell. Yet, recently, it has been found that, in Escherichia coli bacterial cells, a mutation conferring resistance to an antibiotic can be advantageous to the bacterial cell if another antibiotic-resistance mutation is already present, a phenomenon called sign epistasis. Here we study the interaction between antibiotic-resistance chromosomal mutations and conjugative (i.e., self-transmissible) plasmids and find many cases of sign epistasis (40%)--including one of reciprocal sign epistasis where the strain carrying both resistance determinants is fitter than the two strains carrying only one of the determinants. This implies that the acquisition of an additional resistance plasmid or of a resistance mutation often increases the fitness of a bacterial strain already resistant to antibiotics. We further show that there is an overall antagonistic interaction between mutations and plasmids (52%). These results further complicate expectations of resistance reversal by interdiction of antibiotic use.
authors.affiliation: Centro de Biologia Ambiental, Faculdade de Ciências da Universidade de Lisboa, Lisboa, Portugal.
authors.forename: Rui F
authors.initials: RF
authors.lastname: Silva
authors.forename: Sílvia C M
authors.initials: SC
authors.lastname: Mendonça
authors.forename: Luís M
authors.initials: LM
authors.lastname: Carvalho
authors.forename: Ana M
authors.initials: AM
authors.lastname: Reis
authors.forename: Isabel
authors.initials: I
authors.lastname: Gordo
authors.forename: Sandra
authors.initials: S
authors.lastname: Trindade
authors.forename: Francisco
authors.initials: F
authors.lastname: Dionisio
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology; D002876:Chromosomes, Bacterial / Q000235:genetics*; D003227:Conjugation, Genetic; D024881:Drug Resistance, Bacterial / Q000235:genetics*; D004843:Epistasis, Genetic; D004926:Escherichia coli / Q000187:drug effects* / Q000235:genetics*; D029968:Escherichia coli Proteins / Q000235:genetics; D009154:Mutation / Q000235:genetics; D010957:Plasmids / Q000235:genetics*
chemical_list: D000900:Anti-Bacterial Agents; D029968:Escherichia coli Proteins