In Vitro and In Vivo Antibacterial Activities of DW286, a New Fluoronaphthyridone Antibiotic

Abstract

The in vitro and in vivo activities of DW286, a novel fluoronaphthyridone with potent antibacterial activity, were compared with those of ciprofloxacin, gemifloxacin, sparfloxacin, and trovafloxacin. Against gram-positive bacteria, such as Staphylococcus aureus, Staphylococcus epidermidis, Streptococcus pneumoniae, and Enterococcus faecalis, the in vitro activity of DW286 was stronger than that of any other reference antibiotic. Against gram-negative bacteria, the activity of DW286 was similar to those of trovafloxacin and gemifloxacin but was weaker than that of ciprofloxacin. In a mouse systemic infection caused by three S. aureus strains, including methicillin-resistant S. aureus and quinolone-resistant S. aureus (QRSA), DW286 demonstrated the most potent activity, as found in vitro. Specially, DW286 is >8-fold more active against QRSA than the other fluoroquinolones. And the 50% protective doses for DW286 were correspondent with the in vitro activities.The quinolones have evolved from agents used solely for the treatment of urinary tract infections to molecules with potent activity against a wide spectrum of significant bacterial pathogens. Progressive modifications in their molecular configurations have improved both the spectrum and potency of their in vitro activities (2). These compounds have been successfully used in clinics for a decade. The targets in fluoroquinolone research during the last few years include improving the pharmacokinetic properties, increasing the activity against grampositive cocci and anaerobes and against fluoroquinolone-resistant strains, and improving activity against nonfermentative gram-negative species (1,4,5,6). In addition, the increasing pathogen resistance to antimicrobial agents is a cause of concern. This increase in the resistance to fluoroquinolone emphasizes the importance of the continued development of new structural candidates (3,4,5,6,7). The use of newer fluoroquinolone derivatives will potentially contribute to decreasing the spread of resistance to other antimicrobial agents by reducing the selective pressure on other antibiotic groups (5). New candidates have been developed in an attempt to help improve this situation. DW286, 7-[3-(aminomethyl)-4-(methoxyimino)-3-methyltetrahydro-1H-1-pyrrolyl]-1-cyclopropyl-6-fluoro-4-oxo-1, 4-dihydro [1,8]naphthyridine-3-carboxylic acid hydrochloric acid salt, is a novel fluoronaphthyridone antibacterial agent that was synthesized for this purpose (Fig. 1). In this study, we determined the in vitro activity of DW286 in several groups of clinical isolates and compared it with those of ciprofloxacin, gemifloxacin, sparfloxacin, and trovafloxacin. We also compared the in vivo protective efficacy of DW286 with those of the fluoroquinolones against a systemic infection in mice.The studied compounds were obtained as follows: DW286, ciprofloxacin, sparfloxacin, and gemifloxacin were synthesized at the R & D Center, Dong Wha Pharmaceutical Company, Anyang City, Korea. Trovafloxacin was provided by Pfizer Pharmaceuticals, New York,...

Extended Spectrum of Quinolone Resistance, Even to a Potential Latter Third-Generation Agent, as a Result of a Minimum of Two GrlA and Two GyrA Alterations in Quinolone-Resistant <i>Staphylococcus aureus</i>

“…The resistance rate of DW286 in QRSA was only 15.3%, and its in vitro activity was extremely good compared with the earlier third-generation agent, trovafloxacin, for which the resistance rate was 89.8%. The low resistance rate and downward MIC spread of DW286 in QRSA support previous reports that DW286 has better activity against quinolone-susceptible S. aureus as well as QRSA than the earlier third-generation compounds [4,6,7] .…”

“…Ciprofloxacin, from the second generation, is an innovative agent that was able to bypass Gram-positive resistance, and sparfloxacin, the representative latter second-generation agent, shows a broader spectrum of activity, allowing application to respiratory tract infections. The third-generation agent, trovafloxacin, has sufficiently broad activity to even be used effectively against anaerobes, and DW286, a potential latter third-generation agent, has great in vitro antibacterial activity against Gram-positive pathogens, including methicillin-resistant S. aureus and QRSA [4,7] .…”

“…In recent years, major efforts have been made to improve the activity of quinolones against quinolone-resistant Gram-positive pathogens [3] . DW286, a potential latter third-generation agent, has been found to have improved in vitro activity against Gram-positive pathogens, including ciprofloxacin (quinolone)-resistant Staphylococcus aureus (QRSA) and streptococci [4,6,7] .…”

General Pharmacology of DW-286a, a New Fluoronaphthyridone Antibiotic: Effects on Central Nervous, Cardiovascular, and Respiratory Systems

“…8) From a pharmacokinetic point of view, DW286a shows much better efficacy than other quinolone antibiotics in animals. It was demonstrated that the antibacterial activity of DW-286a was superior to that of ciprofloxacin, gemifloxacin, sparfloxacin, and trovafloxacin against quinolone-sensitive Staphylococcus aureus (MIC at which 50% of the isolates tested are inhibited [MIC 50 ]ϭ 0.008 mg/ml; MIC 90 ϭ0.016 mg/ml) and quinolone-resistant S. aureus (QRSA) (MIC 50 ϭ0.5 mg/ml; MIC 90 ϭ8 mg/ml).…”

“…From a pharmacokinetic point of view, DW286a was demonstrated to have much better efficacy than other quinolone antibiotics in animals. 8) In the present study, the general pharmacologic effects of DW-286a on the central nervous, cardiovascular, and respiratory systems were investigated. DW-286a at all doses and time points showed no effects on general behavior (data not shown), motor coordination (Table 1), analgesia (Table 2), seizure and mortality (Table 3), cardiovascular system (Table 4, Fig.…”