Effect of Emergence of Fluoroquinolone Resistance on Intrinsic Expression of P-Glycoprotein Phenotype in Corneal Epithelial Cells

Abstract

Purpose: 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 mg/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.

Mitochondrial Dysfunction in Retinal Diseases

“…A number of possibilities exist for mitochondrial targeted drug delivery such as (i) therapeutic drug targeting based on negative inner membrane potential of mitochondria, (ii) mitochondrial based enzyme catalyze drug release from prodrugs, and (iii) mitochondrial localized transporter or receptor mediated prodrug delivery (Figure 4). 82–86 Continued research in this exciting area will undoubtedly provide a greater understanding of how oxidative stress and deficiencies of the mtDNA contribute to the pathogenesis of neurodegenerative retinal diseases. Future therapeutic strategies should target mitochondria with the ultimate goal of blocking or retarding the effects of chronic mitochondrial dysfunction.…”

Comparison of the Anti-angiogenic and Anti-inflammatory Effects of Two Antibiotics: Clarithromycin Versus Moxifloxacin

“…[35][36][37][38] Transporter-mediated drug absorption is known to be highly variable, even between drugs that are closely related chemically; there would be difference of drug absorption between the moxifloxacin and clarithromycin apart from their general properties related to lipophilicity.…”

Expression of Efflux Transporters in Human Ocular Tissues

“…In 2003, Dey et al (2003) found, for the first time, that the human cornea can express MDR1. Since then, individual efflux transporters in human and animal corneas and corneal epithelial cells have been widely investigated (Karla et al, 2007a(Karla et al, ,b, 2009Pelis et al, 2009;Vellonen et al, 2010;Barot et al, 2011;Li et al, 2012). Functional activity of some efflux transporters has also been evaluated, but the results of efflux transporter expressions and functions were very different.…”