Stationary phase persister formation in Escherichia coli can be suppressed by piperacillin and PBP3 inhibition.

TitleStationary phase persister formation in Escherichia coli can be suppressed by piperacillin and PBP3 inhibition.
Publication TypeJournal Article
Year of Publication2019
AuthorsAedo, SJ, Orman, MA, Brynildsen, MP
JournalBMC Microbiol
Date Published2019 06 24
Keywordsbeta-Lactams, Cell Wall, Drug Resistance, Bacterial, Escherichia coli, Escherichia coli Proteins, Fluoroquinolones, Mutation, Penicillin-Binding Proteins, Peptidoglycan Glycosyltransferase, Phenotype, Piperacillin, Protein Kinases, Transcription Factors

<p><b>BACKGROUND: </b>Persisters are rare phenotypic variants within a bacterial population that are capable of tolerating lethal antibiotic concentrations. Passage through stationary phase is associated with the formation of persisters (type I), and a major physiological response of Escherichia coli during stationary phase is cell wall restructuring. Given the concurrence of these processes, we sought to assess whether perturbation to cell wall synthesis during stationary phase impacts type I persister formation.</p><p><b>RESULTS: </b>We tested a panel of cell wall inhibitors and found that piperacillin, which primarily targets penicillin binding protein 3 (PBP3 encoded by ftsI), resulted in a significant reduction in both β-lactam (ampicillin, carbenicillin) and fluoroquinolone (ofloxacin, ciprofloxacin) persister levels. Further analyses showed that piperacillin exposure through stationary phase resulted in cells with more ATP, DNA, RNA, and protein (including PBPs) than untreated controls; and that their physiology led to more rapid resumption of DNA gyrase supercoiling activity, translation, and cell division upon introduction into fresh media. Previously, PBP3 inhibition had been linked to antibiotic efficacy through the DpiBA two component system; however, piperacillin suppressed persister formation in ΔdpiA to the same extent as it did in wild-type, suggesting that DpiBA is not required for the phenomenon reported here. To test the generality of PBP3 inhibition on persister formation, we expressed FtsI Ser307Ala to genetically inhibit PBP3, and suppression of persister formation was also observed, although not to the same magnitude as that seen for piperacillin treatment.</p><p><b>CONCLUSIONS: </b>From these data we conclude that stationary phase PBP3 activity is important to type I persister formation in E. coli.</p>

Alternate JournalBMC Microbiol.
PubMed ID31234796
PubMed Central IDPMC6591824
Grant ListR21 AI115075 / AI / NIAID NIH HHS / United States
R21 AI117009 / AI / NIAID NIH HHS / United States