title: Effect of emergence of fluoroquinolone resistance on intrinsic expression of P-glycoprotein phenotype in corneal epithelial cells.
abstract: OBJECTIVE
  Multidrug resistance (MDR) represents a major obstacle to the success of antimicrobial fluoroquinolone (FQ) therapy. MDR-associated efflux protein pumps antimicrobial agents out of the corneal cells, leading to suboptimal eradication of microbes. This article examines whether long-term FQ (levofloxacin, ofloxacin, and gatifloxacin) therapy can modify the MDR phenotype (P-glycoprotein [P-gp]) on corneal epithelial cells (Statens Seruminstitut Rabbit Cornea [SIRC]).
  
  
  METHODS
  To study the effect of FQ, SIRC cells without any exposure to FQ (control) were compared with the cells exposed to ofloxacin, levofloxacin, and gatifloxacin at a concentration of 10 μg/mL for 3 weeks. Efflux activity of P-gp was assessed by in vitro uptake studies (fluorescent and radioactive), flow cytometry, and quantitative real-time polymerase chain reaction (qRT-PCR).
  
  
  RESULTS
  In the presence of FQ, elevated P-gp expression was noted with uptake, flow cytometry, and qRT-PCR analyses. This study confirms that long-term exposure to antibiotics, particularly FQ, can induce overexpression of P-gp efflux transporter present on the corneal cells. P-gp overexpression is commonly noticed in anticancer drug resistance cell lines; however, for the first time, this report describes overexpression of P-gp due to FQ exposure.
  
  
  CONCLUSIONS
  Based on this result, it is suggested that strategies should be developed and implemented not only to overcome resistance to ocular pathogen but also to FQ-induced cellular resistance.
authors.affiliation: Division of Pharmaceutical Sciences, School of Pharmacy, University of Missouri, Kansas City, Missouri 64108, USA.
authors.forename: Megha
authors.initials: M
authors.lastname: Barot
authors.forename: Mitan R
authors.initials: MR
authors.lastname: Gokulgandhi
authors.forename: Megan
authors.initials: M
authors.lastname: Haghnegahdar
authors.forename: Pranjali
authors.initials: P
authors.lastname: Dalvi
authors.forename: Ashim K
authors.initials: AK
authors.lastname: Mitra
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics*; D000818:Animals; D002460:Cell Line; D003315:Cornea / Q000187:drug effects* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D024901:Drug Resistance, Multiple, Bacterial; D004847:Epithelial Cells / Q000187:drug effects* / Q000378:metabolism; D005434:Flow Cytometry; D024841:Fluoroquinolones / Q000008:administration & dosage / Q000494:pharmacology*; D015870:Gene Expression / Q000187:drug effects; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics; D011817:Rabbits; D060888:Real-Time Polymerase Chain Reaction
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D024841:Fluoroquinolones; D027425:ATP-Binding Cassette, Sub-Family C Proteins