title: Fitness trade-offs explain low levels of persister cells in the opportunistic pathogen Pseudomonas aeruginosa.
abstract: Microbial populations often contain a fraction of slow-growing persister cells that withstand antibiotics and other stress factors. Current theoretical models predict that persistence levels should reflect a stable state in which the survival advantage of persisters under adverse conditions is balanced with the direct growth cost impaired under favourable growth conditions, caused by the nonreplication of persister cells. Based on this direct growth cost alone, however, it remains challenging to explain the observed low levels of persistence (<<1%) seen in the populations of many species. Here, we present data from the opportunistic human pathogen Pseudomonas aeruginosa that can explain this discrepancy by revealing various previously unknown costs of persistence. In particular, we show that in the absence of antibiotic stress, increased persistence is traded off against a lengthened lag phase as well as a reduced survival ability during stationary phase. We argue that these pleiotropic costs contribute to the very low proportions of persister cells observed among natural P. aeruginosa isolates (3 × 10(-8) -3 × 10(-4)) and that they can explain why strains with higher proportions of persister cells lose out very quickly in competition assays under favourable growth conditions, despite a negligible difference in maximal growth rate. We discuss how incorporating these trade-offs could lead to models that can better explain the evolution of persistence in nature and facilitate the rational design of alternative therapeutic strategies for treating infectious diseases.
authors.affiliation: Centre of Microbial and Plant Genetics, KU Leuven - University of Leuven, Kasteelpark Arenberg 20 bus 2460, 3001 Leuven, Belgium.
authors.forename: Kristine
authors.initials: K
authors.lastname: Stepanyan
authors.forename: Tom
authors.initials: T
authors.lastname: Wenseleers
authors.forename: Edgar A
authors.initials: EA
authors.lastname: Duéñez-Guzmán
authors.forename: Frédéric
authors.initials: F
authors.lastname: Muratori
authors.forename: Bram
authors.initials: B
authors.lastname: Van den Bergh
authors.forename: Natalie
authors.initials: N
authors.lastname: Verstraeten
authors.forename: Luc
authors.initials: L
authors.lastname: De Meester
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Verstrepen
authors.forename: Maarten
authors.initials: M
authors.lastname: Fauvart
authors.forename: Jan
authors.initials: J
authors.lastname: Michiels
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology; D024881:Drug Resistance, Bacterial / Q000235:genetics*; D019143:Evolution, Molecular; D056084:Genetic Fitness; D014644:Genetic Variation; D011550:Pseudomonas aeruginosa / Q000187:drug effects / Q000235:genetics*
chemical_list: D000900:Anti-Bacterial Agents
keywords: Pseudomonas aeruginosa; evolutionarily stable strategy; persistence; pleiotropy