Contributions of the 8-Methoxy Group of Gatifloxacin to Resistance Selectivity, Target Preference, and Antibacterial Activity against Streptococcus pneumoniae

Abstract

Gatifloxacin (8-methoxy, 7-piperazinyl-3-methyl) at the MIC selected mutant strains that possessed gyrA mutations at a low frequency (3.7 ؋ 10 ؊9 ) from wild-type strain Streptococcus pneumoniae IID553. AM-1147 (8-methoxy, 7-piperazinyl-3-H) at the MIC or higher concentrations selected no mutant strains. On the other hand, the respective 8-H counterparts of these two compounds, AM-1121 (8-H, 7-piperazinyl-3-methyl) and ciprofloxacin (8-H, 7-piperazinyl-3-H), at one and two times the MIC selected mutant strains that possessed parC mutations at a high frequency (>2.4 ؋ 10 ؊6 ). The MIC of AM-1147 increased for the gyrA mutant strains but not for the parC mutant strains compared with that for the wild-type strain. These results suggest that fluoroquinolones that harbor 8-methoxy groups select mutant strains less frequently and prefer DNA gyrase, as distinct from their 8-H counterparts. The in vitro activities of gatifloxacin and AM-1147 are twofold higher against the wild-type strain, eight-and twofold higher against the first-step parC and gyrA mutant strains, respectively, and two-to eightfold higher against the second-step gyrA and parC double mutant strains than those of their 8-H counterparts. These results indicate that the 8-methoxy group contributes to enhancement of antibacterial activity against target-altered mutant strains as well as the wild-type strain. It is hypothesized that the 8-methoxy group of gatifloxacin increases the level of target inhibition, especially against DNA gyrase, so that it is nearly the same as that for topoisomerase IV inhibition in the bacterial cell, leading to potent antibacterial activity and a low level of resistance selectivity.

Penetration of second-, third-, and fourth-generation topical fluoroquinolone into aqueous and vitreous humour in a rabbit endophthalmitis model

“…The alterations to the structure of the older-generation fluoroquinolones improve the spectrum of activity of fourth-generation fluoroquinolones to include strains of Staphylococcus and Streptococcus and species otherwise resistant to older-generation fluoroquinolones. 23,24 These new fourth-generation fluoroquinolones are particularly needed because the incidence of endophthalmitis is on the rise, 22,25 especially after clear corneal incision cataract surgery. 22,26 It has been demonstrated that perioperative treatment with a prior-generation fluoroquinolone is efficacious in eliminating bacteria found in the external ocular adnexa, the most likely source of the inoculum of bacteria during cataract surgery.…”

Prevalence of Single Mutations in Topoisomerase Type II Genes among Levofloxacin-Susceptible Clinical Strains of Streptococcus pneumoniae Isolated in the United States in 1992 to 1996 and 1999 to 2000

“…Of particular interest is whether the recent introduction into the clinic of gatifloxacin, a fluoroquinolone that has DNA gyrase (gyrA/B) as its primary target (5), and moxifloxacin, which may target DNA gyrase (6), will affect the prevalence and profile of single QRDR mutants. According to their mechanisms of action, gatifloxacin and moxifloxacin would be expected to select preferentially for gyr (A/B) mutations (5,6). It remains to be determined how the addition of DNA gyrase single mutants into a population that already contains topoisomerase IV single mutants will affect the emergence of fluoroquinolone-resistant strains within S. pneumoniae, a species known to efficiently exchange DNA by transformation.…”

Activities of Mutant Prevention Concentration-Targeted Moxifloxacin and Levofloxacin against Streptococcus pneumoniae in an In Vitro Pharmacodynamic Model

“…It is thought that the C-8-OMe functionality of moxifloxacin confers a dual targeting of topoisomerase IV and DNA gyrase, thus helping to explain the effect of this functional group in restricting selection of resistant organisms (11,26,27). Levofloxacin, in contrast, appears to preferentially target topoisomerase IV in S. pneumoniae.…”