title: The innate growth bistability and fitness landscapes of antibiotic-resistant bacteria.
abstract: To predict the emergence of antibiotic resistance, quantitative relations must be established between the fitness of drug-resistant organisms and the molecular mechanisms conferring resistance. These relations are often unknown and may depend on the state of bacterial growth. To bridge this gap, we have investigated Escherichia coli strains expressing resistance to translation-inhibiting antibiotics. We show that resistance expression and drug inhibition are linked in a positive feedback loop arising from an innate, global effect of drug-inhibited growth on gene expression. A quantitative model of bacterial growth based on this innate feedback accurately predicts the rich phenomena observed: a plateau-shaped fitness landscape, with an abrupt drop in the growth rates of cultures at a threshold drug concentration, and the coexistence of growing and nongrowing populations, that is, growth bistability, below the threshold.
authors.affiliation: Department of Physics, University of California at San Diego, La Jolla, CA 92093-0374, USA.
authors.forename: J Barrett
authors.initials: JB
authors.lastname: Deris
authors.forename: Minsu
authors.initials: M
authors.lastname: Kim
authors.forename: Zhongge
authors.initials: Z
authors.lastname: Zhang
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Okano
authors.forename: Rutger
authors.initials: R
authors.lastname: Hermsen
authors.forename: Alexander
authors.initials: A
authors.lastname: Groisman
authors.forename: Terence
authors.initials: T
authors.lastname: Hwa
mesh_terms: D000222:Adaptation, Physiological; D002701:Chloramphenicol / Q000378:metabolism / Q000494:pharmacology; D015500:Chloramphenicol O-Acetyltransferase / Q000096:biosynthesis; D024881:Drug Resistance, Bacterial; D004926:Escherichia coli / Q000187:drug effects* / Q000235:genetics / Q000254:growth & development*; D015964:Gene Expression Regulation, Bacterial / Q000187:drug effects; D056084:Genetic Fitness; D008954:Models, Biological; D014176:Protein Biosynthesis / Q000187:drug effects; D011500:Protein Synthesis Inhibitors / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D011500:Protein Synthesis Inhibitors; D002701:Chloramphenicol; D015500:Chloramphenicol O-Acetyltransferase