title: The fitness costs and trade-off shapes associated with the exclusion of nine antibiotics by OmpF porin channels.
abstract: The trade-off relationship between antibiotic exclusion and nutrient access across the Gram-negative outer membrane is determined by structural constraints in porin channels. The precise nutritional cost of exclusion is unknown for different antibiotics, as are the shapes of the nutrition-susceptibility trade-off. Using a library of 10 engineered isogenic Escherichia coli strains with structural modifications of OmpF porin expressed at a constant level, susceptibilities were measured for nine antibiotics and the nutritional fitness costs estimated by competitions in chemostats. Different antibiotics exhibited a remarkably varied range of geometries in the nutrition-susceptibility trade-off, including convex, concave and sigmoidal trade-off shapes. The trade-off patterns predict the possibility of adaptations in contributing to antibiotic resistance; exclusion of amoxicillin or trimethoprim in ompF mutants can occur with little loss of fitness whereas kanamycin and streptomycin exclusion has a high cost. Some individual OmpF changes even allow positive correlations (trade-ups), resulting in increased fitness and decreased susceptibility specifically to cephalexin or ciprofloxacin. The surprising plasticity of the nutrition-exclusion relationship means that there are no generalisable rules that apply to decreasing susceptibility for all antibiotics. The protein changes are exquisitely specific in determining nutritional fitness and adaptive outcomes in a structural constraint trade-off.
authors.affiliation: School of Life and Environmental Sciences, University of Sydney, Sydney, New South Wales, Australia.
authors.forename: Katherine
authors.initials: K
authors.lastname: Phan
authors.affiliation: School of Life and Environmental Sciences, University of Sydney, Sydney, New South Wales, Australia.
authors.forename: Thomas
authors.initials: T
authors.lastname: Ferenci
mesh_terms: D000222:Adaptation, Physiological / Q000187:drug effects; D000900:Anti-Bacterial Agents / Q000378:metabolism* / Q000494:pharmacology; D024901:Drug Resistance, Multiple, Bacterial; D004926:Escherichia coli / Q000187:drug effects / Q000378:metabolism*; D056084:Genetic Fitness; D018272:Porins / Q000378:metabolism*
chemical_list: D000900:Anti-Bacterial Agents; C109237:OmpF protein; D018272:Porins