title: Genome-wide analysis captures the determinants of the antibiotic cross-resistance interaction network.
abstract: Understanding how evolution of antimicrobial resistance increases resistance to other drugs is a challenge of profound importance. By combining experimental evolution and genome sequencing of 63 laboratory-evolved lines, we charted a map of cross-resistance interactions between antibiotics in Escherichia coli, and explored the driving evolutionary principles. Here, we show that (1) convergent molecular evolution is prevalent across antibiotic treatments, (2) resistance conferring mutations simultaneously enhance sensitivity to many other drugs and (3) 27% of the accumulated mutations generate proteins with compromised activities, suggesting that antibiotic adaptation can partly be achieved without gain of novel function. By using knowledge on antibiotic properties, we examined the determinants of cross-resistance and identified chemogenomic profile similarity between antibiotics as the strongest predictor. In contrast, cross-resistance between two antibiotics is independent of whether they show synergistic effects in combination. These results have important implications on the development of novel antimicrobial strategies.
authors.affiliation: 1] Synthetic and Systems Biology Unit, Institute of Biochemistry, Biological Research Centre, Temesvari krt 62, Szeged 6726, Hungary [2].
authors.forename: Viktória
authors.initials: V
authors.lastname: Lázár
authors.affiliation: 1] Sequencing Platform, Institute of Biochemistry, Biological Research Centre, Temesvari krt 62, Szeged 6726, Hungary [2].
authors.forename: István
authors.initials: I
authors.lastname: Nagy
authors.affiliation: 1] Synthetic and Systems Biology Unit, Institute of Biochemistry, Biological Research Centre, Temesvari krt 62, Szeged 6726, Hungary [2].
authors.forename: Réka
authors.initials: R
authors.lastname: Spohn
authors.affiliation: Synthetic and Systems Biology Unit, Institute of Biochemistry, Biological Research Centre, Temesvari krt 62, Szeged 6726, Hungary.
authors.forename: Bálint
authors.initials: B
authors.lastname: Csörgő
authors.affiliation: Synthetic and Systems Biology Unit, Institute of Biochemistry, Biological Research Centre, Temesvari krt 62, Szeged 6726, Hungary.
authors.forename: Ádám
authors.initials: Á
authors.lastname: Györkei
authors.affiliation: Synthetic and Systems Biology Unit, Institute of Biochemistry, Biological Research Centre, Temesvari krt 62, Szeged 6726, Hungary.
authors.forename: Ákos
authors.initials: Á
authors.lastname: Nyerges
authors.affiliation: Sequencing Platform, Institute of Biochemistry, Biological Research Centre, Temesvari krt 62, Szeged 6726, Hungary.
authors.forename: Balázs
authors.initials: B
authors.lastname: Horváth
authors.affiliation: Sequencing Platform, Institute of Biochemistry, Biological Research Centre, Temesvari krt 62, Szeged 6726, Hungary.
authors.forename: Andrea
authors.initials: A
authors.lastname: Vörös
authors.affiliation: MTA-SZTE Research Group on Artificial Intelligence, Tisza Lajos krt 103., H-6720 Szeged, Hungary.
authors.forename: Róbert
authors.initials: R
authors.lastname: Busa-Fekete
authors.affiliation: Synthetic and Systems Biology Unit, Institute of Biochemistry, Biological Research Centre, Temesvari krt 62, Szeged 6726, Hungary.
authors.forename: Mónika
authors.initials: M
authors.lastname: Hrtyan
authors.affiliation: Synthetic and Systems Biology Unit, Institute of Biochemistry, Biological Research Centre, Temesvari krt 62, Szeged 6726, Hungary.
authors.forename: Balázs
authors.initials: B
authors.lastname: Bogos
authors.affiliation: Synthetic and Systems Biology Unit, Institute of Biochemistry, Biological Research Centre, Temesvari krt 62, Szeged 6726, Hungary.
authors.forename: Orsolya
authors.initials: O
authors.lastname: Méhi
authors.affiliation: Synthetic and Systems Biology Unit, Institute of Biochemistry, Biological Research Centre, Temesvari krt 62, Szeged 6726, Hungary.
authors.forename: Gergely
authors.initials: G
authors.lastname: Fekete
authors.affiliation: Synthetic and Systems Biology Unit, Institute of Biochemistry, Biological Research Centre, Temesvari krt 62, Szeged 6726, Hungary.
authors.forename: Balázs
authors.initials: B
authors.lastname: Szappanos
authors.affiliation: Linear Accelerator Laboratory, University of Paris-Sud, CNRS, Orsay 91898, France.
authors.forename: Balázs
authors.initials: B
authors.lastname: Kégl
authors.affiliation: Synthetic and Systems Biology Unit, Institute of Biochemistry, Biological Research Centre, Temesvari krt 62, Szeged 6726, Hungary.
authors.forename: Balázs
authors.initials: B
authors.lastname: Papp
authors.affiliation: Synthetic and Systems Biology Unit, Institute of Biochemistry, Biological Research Centre, Temesvari krt 62, Szeged 6726, Hungary.
authors.forename: Csaba
authors.initials: C
authors.lastname: Pál
mesh_terms: D000220:Adaptation, Biological / Q000235:genetics; D024901:Drug Resistance, Multiple, Bacterial / Q000235:genetics*; D004926:Escherichia coli / Q000235:genetics*; D019143:Evolution, Molecular; D016680:Genome, Bacterial; D009154:Mutation; D012641:Selection, Genetic; D017422:Sequence Analysis, DNA