title: Influence ofrhlRandlasRon Polymyxin Pharmacodynamics in Pseudomonas aeruginosa and Implications for Quorum Sensing Inhibition with Azithromycin.
abstract: The impact of quorum sensing on polymyxin and azithromycin pharmacodynamics was assessed inPseudomonas aeruginosaPAO1 and an isogenicrhlR/lasRdouble knockout. For polymyxin B, greater killing against therhlR/lasRknockout than against PAO1 was observed at 108CFU/ml (polymyxin B half-maximal effective concentration [EC50], 5.61 versus 12.5 mg/liter, respectively;P< 0.005). Polymyxin B combined with azithromycin (256 mg/liter) was synergistic against each strain, significantly reducing the respective polymyxin B EC50compared to those with monotherapy (P< 0.005), and is a promising strategy by which to combatP. aeruginosa.
authors.affiliation: Laboratory for Antimicrobial Pharmacodynamics, University at Buffalo School of Pharmacy and Pharmaceutical Sciences, Buffalo, New York, USA.|New York State Center of Excellence in Life Sciences and Bioinformatics, Buffalo, New York, USA.
authors.forename: Zackery P
authors.initials: ZP
authors.lastname: Bulman
authors.affiliation: Laboratory for Antimicrobial Pharmacodynamics, University at Buffalo School of Pharmacy and Pharmaceutical Sciences, Buffalo, New York, USA.|New York State Center of Excellence in Life Sciences and Bioinformatics, Buffalo, New York, USA.
authors.forename: Neang S
authors.identifier: 0000-0002-5571-0347
authors.initials: NS
authors.lastname: Ly
authors.affiliation: California Northstate University College of Pharmacy, Elk Grove, California, USA.
authors.forename: Justin R
authors.initials: JR
authors.lastname: Lenhard
authors.affiliation: Laboratory for Antimicrobial Pharmacodynamics, University at Buffalo School of Pharmacy and Pharmaceutical Sciences, Buffalo, New York, USA.|New York State Center of Excellence in Life Sciences and Bioinformatics, Buffalo, New York, USA.
authors.forename: Patricia N
authors.initials: PN
authors.lastname: Holden
authors.affiliation: Center for Pharmacometrics and Systems Pharmacology, Department of Pharmaceutics, College of Pharmacy, University of Florida, Orlando, Florida, USA.
authors.forename: Jürgen B
authors.initials: JB
authors.lastname: Bulitta
authors.affiliation: Laboratory for Antimicrobial Pharmacodynamics, University at Buffalo School of Pharmacy and Pharmaceutical Sciences, Buffalo, New York, USA btsuji@buffalo.edu.|New York State Center of Excellence in Life Sciences and Bioinformatics, Buffalo, New York, USA.
authors.forename: Brian T
authors.initials: BT
authors.lastname: Tsuji
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology; D017963:Azithromycin / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000235:genetics* / Q000378:metabolism; D015169:Colony Count, Microbial; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D004357:Drug Synergism; D015964:Gene Expression Regulation, Bacterial; D020128:Inhibitory Concentration 50; D011112:Polymyxin B / Q000494:pharmacology*; D011550:Pseudomonas aeruginosa / Q000187:drug effects* / Q000235:genetics / Q000254:growth & development / Q000378:metabolism; D053038:Quorum Sensing / Q000187:drug effects* / Q000235:genetics; D015534:Trans-Activators / Q000172:deficiency / Q000235:genetics*
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D004338:Drug Combinations; C080365:LasR protein, Pseudomonas aeruginosa; C086515:RhlR protein, Pseudomonas aeruginosa; D015534:Trans-Activators; D017963:Azithromycin; D011112:Polymyxin B
keywords: P. aeruginosa; Pseudomonas aeruginosa; azithromycin; colistin; mechanism-based modeling; pharmacodynamics; polymyxin B; polymyxins; quorum sensing