Contribution of the R8 substituent to the in vitro antibacterial potency of besifloxacin and comparator ophthalmic fluoroquinolones

Abstract

IntroductionPrevious work has shown that besifloxacin, an 8-chloro-fluoroquinolone, has more potent activity against gram-positive pathogens than moxifloxacin and gatifloxacin, which carry an 8-methoxy group. This study was conducted to determine the contribution of the R7 and R8 substituent to fluoroquinolone antibacterial activity.Materials and methodsBesifloxacin, moxifloxacin, gatifloxacin, their R8 structural analogs, and ciprofloxacin were tested against representative isolates of various gram-positive and gram-negative species and previously characterized fluoroquinolone-resistant mutants of Staphylococcus aureus. Minimum inhibitory and minimum bactericidal concentrations were determined according to Clinical and Laboratory Standards Institute (CLSI) guidelines. Reserpine was used to determine the effect of efflux pumps on antibacterial activity.ResultsIn general, exchanging the R8 residue in besifloxacin slightly reduced the molecule’s potency, while introducing an 8-chloro group in moxifloxacin increased its potency. A similar change in gatifloxacin had little to no effect. Substituting the R8 residues did not increase the susceptibility to the efflux pump inhibitor reserpine or result in a loss of bactericidal activity. In contrast, the positive control, ciprofloxacin, was shown to be a substrate for reserpine and lost bactericidal activity against some fluoroquinolone-resistant isolates of S. aureus.ConclusionThe data presented here show that, depending on the R7 substituent, replacing an 8-methoxy group with an 8-chloro substituent can improve potency or can have little-to-no effect. These findings highlight the importance of the interplay between the R7 and R8 substituents in determining antibacterial potency.

Surveillance of the Activity of Aminoglycosides and Fluoroquinolones Against Ophthalmic Pathogens from Europe in 2010–2011

“…16,21 Members of the fluoroquinolone family differ in their chemical structure, especially in their R7 and R8 substituents, which is thought to allow some fluoroquinolones to bind more strongly to their target molecules than others. 22 Differences in affinities between the antibiotic and the target could explain why ciprofloxacin was the most potent fluoroquinolone against P. aeruginosa, but the least potent against S. aureus, and why besifloxacin was more potent against fluoroquinolone-resistant MRCoNS than moxifloxacin. While isolates that are highly resistant to ciprofloxacin will also be nonsusceptible to other fluoroquinolones, strains that show a low level of ciprofloxacin-resistance might still be treatable with more potent alternatives of the same drug family, especially when applied topically where higher drug concentrations at the site of action can be achieved.…”

Physicochemical investigation of antibacterial Moxifloxacin interacting with quaternary ammonium disinfectants

“…The origin of this characteristic feature of MOF can be ascribed to its wide range of activities against several pathogenic gram-positive and gram-negative bacteria including atypical respiratory pathogens [24][25][26][27]. In addition, MOF exhibit 40-50% protein binding and show greater affinity for the A subunit of DNA gyrase.…”

Besifloxacin: Efficacy and Safety in Treatment and Prevention of Ocular Bacterial Infections

“…Fluoroquinolones (FQs) have been successfully used in ophthalmology for nearly two decades, thanks in large part to a series of incremental improvements in their antimicrobial activity and pharmacokinetic profiles [ 1 ]. Today, treatment for bacterial ocular surface infections—including conjunctivitis, blepharitis, and keratitis—is largely empirical; the FQs’ broad-spectrum antimicrobial activity and documented safety and lack of toxicity make them well suited to empirical therapy [ 2 – 4 ]. With activity against a broad spectrum of bacterial pathogens including Gram-positive, Gram-negative and anaerobic organisms [ 1 , 5 ], current-generation FQs, such as gatifloxacin, moxifloxacin, and besifloxacin, have become first-line agents for the treatment and prevention of bacterial ocular infections [ 6 , 7 ].…”

“…A 0.6% besifloxacin ophthalmic suspension (Besivance ® , Bausch + Lomb, Rochester, NY, USA) was approved in the US and Canada for the treatment of bacterial conjunctivitis in 2009 [ 15 , 16 ]. The first topical chlorofluoroquinolone, besifloxacin has a unique molecular structure designed to confer increased antibacterial potency [ 4 , 17 ]. In susceptibility assays, besifloxacin demonstrated potent in vitro activity against a wide range of pathogens, including those that are resistant to other FQs and antibacterial classes [ 5 ].…”