JAC Advance Access originally published online on April 7, 2006
Journal of Antimicrobial Chemotherapy 2006 57(6):1256-1258; doi:10.1093/jac/dkl144
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Correspondence |
Antimicrobial activity of DW-224a, a new fluoroquinolone, against Streptococcus pneumoniae
1 School of Life and Food Sciences, Handong Global University Pohang, Korea 2 Dong Wha Pharmaceutical Industry Co. Ltd. Anyang, Korea
*Corresponding author. Tel: +82-54-260-1353; Fax: +82-54-260-1925; E-mail: jhkwak{at}handong.edu
Keywords: antimicrobial activity , MICs , post-antibiotic effect
Sir,
DW-224a is a novel fluoroquinolone that is under clinical development and has the formula {1-cyclopropyl-6-fluoro-7-[8-(methoxyimino)-2,6-diazaspiro[3,4]oct-6-yl]-4-oxo-1,4-dihydro[1,8]naphthyridine-3-carboxylic acid hydrochloride}. This compound showed a broad-spectrum antibacterial activity, and it had enhanced activity against Gram-positive organisms, particularly Streptococcus pneumoniae, including strains of pneumococci resistant to other fluoroquinolones.1 Therefore, DW-224a with its expanded antipneumococcal activity might be very useful for the treatment of community-acquired respiratory tract infections.
It is well known that the bactericidal effect of fluoroquinolones is attributed to the inhibition of bacterial DNA gyrase (bacterial topoisomerase II), an enzyme that regulates supercoiling and uncoiling of DNA,2 and it has been demonstrated that the exposure of bacterial pathogens to fluoroquinolones during antimicrobial therapy can select for resistant strains with mutations within the quinolone resistance determining region (QRDR) of the genes encoding DNA gyrase.3
In the present study, we examined the bactericidal activities of DW-224a and comparator fluoroquinolones (gemifloxacin and ciprofloxacin) against S. pneumoniae strains. Especially, we tested well-characterized S. pneumoniae mutant strains (DNA gyrase mutants) to examine the effects of mutations in the gene encoding DNA gyrase on the bactericidal activity of DW-224a and the other fluoroquinolones. We compared the MBC and the post-antibiotic effect (PAE) of DW-224a with those of comparator fluoroquinolones against S. pneumoniae c9211, Staphylococcus aureus 6538p and Escherichia coli 3190Y.
Strains used for time–kill analyses were S. pneumoniae c9211, S. pneumoniae DM1 and S. pneumoniae DM1-1. S. pneumoniae c9211 is a genetically defined parental strain, which was used to select for all mutant strains resistant to DW-286a.4 DM-1 is a quinolone resistant mutant with a single-point change within the QRDR of DNA gyrase (gyrA) at Ser-83 (Ser-83
Tyr). DM1-1 is another gyrA mutant (Ser-83Phe).
The time–kill analyses were performed by the method of the National Committee for Clinical Laboratory Standards M26-A.5 S. pneumoniae strains, incubated in Todd–Hewitt broth with 0.125% yeast extract for 18 h at 37°C, were diluted with fresh broth to 
105 cfu/mL, and the diluted cultures were pre-incubated for 2 h. Each drug was added to the cultures at concentrations of 0.25x, 0.5x, 1x, 2x and 4x the MIC. Aliquots (0.1 mL) of the cultures were removed at 0, 2, 4, 6 and 24 h of incubation. The number of viable cells was determined on drug-free Mueller–Hinton agar (MHA) with 5% defibrinated sheep blood after 24 h of incubation. The MBC was also determined by subculturing 0.1 mL of culture broth onto antibiotic-free MHA plates and antibiotic-supplemented MHA plates. MBC was defined as the lowest concentration bringing about a 99.9% reduction in cfu after 18 h of incubation at 37°C.
The MICs of DW-224a, gemifloxacin and ciprofloxacin for each strain are shown in Figure 1. DW-224a, at concentrations of 2x MIC or 4x MIC, showed a rapid bactericidal activity against S. pneumoniae c9211, DM1 and DM1-1 (Figure 1a–c, respectively). There was at least a 2 log10 decrease in cfu within 4 h at 2x and 4x the MIC of DW-224a. The regrowth of test organisms was prevented completely by DW-224a at concentrations of 1x, 2x and 4x MIC by 24 h, although regrowth occurred in the presence of ciprofloxacin at 1x MIC concentration. DW-224a also showed a dose-dependent bactericidal activity against all test organisms up to 4x the MIC. The MBCs of DW-224a in Mueller–Hinton broth (MHB) were identical to 1x MIC or at most twice the MIC for all strains tested. Because the bactericidal activities of DW-224a increased with increasing concentrations (up to a concentration of 2 mg/L) for all test strains, and because the slope of the lines (rate of activity) in the time–kill curve varied with concentration, we concluded that DW-224a had concentration-dependent bactericidal activities regardless of the tested strains. Mutations within QRDR of the genes encoding DNA gyrase in S. pneumoniae strains did not affect the bactericidal activities of DW-224a, ciprofloxacin and gemifloxacin.
|
PAE of DW-224a was determined using a broth technique in MHB.6 The PAE was calculated by the following equation: PAE = T – C, where T is the time to achieve 1 log10 cfu/mL growth for the antibiotic-exposed sample and C is the time to achieve 1 log10 cfu/mL growth for the untreated control sample (Table 1).
|
In summary, DW-224a showed very potent and dose-dependent bactericidal effect against all strains tested. The clinical usefulness of DW-224a should be established by further studies.
Transparency declarations
None to declare.
Acknowledgements
This study was supported by a grant from the Korea Health 21 R&D Project, Ministry of Health & Welfare, Republic of Korea (01-PJ1-PG4-01PT01-0013).
References
1 Kwak JH, Seol MJ, Kim HJ, et al. (2003) In vitro and in vivo antibacterial activities of the new fluoroquinolone, DW-224a. Programs and Abstracts of the Forty-third Interscience Conference on Antimicrobial Agents and ChemotherapyChicago, IL (American Society for Microbiology, Washington, DC, USA) Abstract F-415, p. 222.
2 Hooper DC. (2001) Mechanisms of action of antimicrobials: focus on fluoroquinolones. Clin Infect Dis 32:Suppl 1, S9–15.
3
Weigel LM, Anderson GJ, Facklam RR, et al. (2001) Genetic analyses of mutations contributing to fluoroquinolone resistance in clinical isolates of Streptococcus pneumoniae. Antimicrob Agents Chemother 45:3517–23.
4 Kwak JH, Seol MJ, So MK, et al. (2002) In vitro development of resistant mutants to DW-286a, a new quinolone antibiotic, in Streptococcus pneumoniae. Programs and Abstracts of the Forty-second Interscience Conference on Antimicrobial Agents and ChemotherapySan Diego, CA (American Society for Microbiology, Washington, DC, USA) Abstract F-578, p. 191.
5 National Committee for Clinical Laboratory Standards. (1999) Methods for Determining Bactericidal Activity of Antimicrobial Agents; Document M26-A (NCCLS, Wayne, PA, USA).
6 Craig WA and Gudmundsson S. (1996) The postantibiotic effect. In Lorian V (Ed.). Antibiotics in Laboratory Medicine Baltimore: Williams & Wilkins pp. 296–329.
CiteULike 
Connotea 
Del.icio.us What's this?
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||