In vitro and in vivo antibacterial activities of T-3761, a new quinolone derivative

Fukuoka, Yoshikazu; Ikeda, Yasushi; Yamashiro, Yoshiko; Takahata, Masahiro; Todo, Yozo; Narita, Hirokazu

doi:10.1128/aac.37.3.384

Cited by 48 publications

(22 citation statements)

References 11 publications

(11 reference statements)

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“…Microscopically, both pathogens were seen to grow as a biofilm on the inside and the outside of the catheter, and it is likely that this mode of growth in some way impeded the effectiveness of the drug, although the exact mechanism behind this impedance was not identified. The therapeutic efficacy of ciprofloxacin against UTI including foreign body-associated UTI caused by several uropathogens has been shown previously (13,39,46). Our results are consistent with previous observations.…”

Section: Discussionsupporting

confidence: 83%

“…Treatment of animals with catheter-associated infection commenced 2 days after bacterial challenge with a dose of 30 mg/kg of body weight ciprofloxacin given orally in 0.2 ml of water twice daily for four consecutive days. This dose of ciprofloxacin was previously shown to have bactericidal effect against several uropathogens in mouse models of experimental UTI (13,39,46). A second group of animals served as an untreated infection control group by being implanted with infected catheters and treated with saline.…”

Section: Methodsmentioning

confidence: 99%

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Noninvasive Biophotonic Imaging for Monitoring of Catheter-Associated Urinary Tract Infections and Therapy in Mice

Kadurugamuwa¹,

Modi²,

Yu³

et al. 2005

Infect Immun

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Urinary tract infections (UTIs) are among the most common bacterial infections acquired by humans, particularly in catheterized patients. A major problem with catheterization is the formation of bacterial biofilms on catheter material and the risk of developing persistent UTIs that are difficult to monitor and eradicate. To better understand the course of UTIs and allow more accurate studies of in vivo antibiotic efficacy, we developed a catheter-based biofilm infection model with mice, using bioluminescently engineered bacteria. Two important urinary tract pathogens, Pseudomonas aeruginosa and Proteus mirabilis, were made bioluminescent by stable insertion of a complete lux operon. Segments of catheter material (precolonized or postimplant infected) with either pathogen were placed transurethrally in the lumen of the bladder by using a metal stylet without surgical manipulation. The bioluminescent strains were sufficiently bright to be readily monitored from the outside of infected animals, using a low-light optical imaging system, including the ability to trace the ascending pattern of light-emitting bacteria through ureters to the kidneys. Placement of the catheter in the bladder not only resulted in the development of strong cystitis that persisted significantly longer than in mice challenged with bacterial suspensions alone but also required prolonged antibiotic treatment to reduce the level of infection. Treatment of infected mice for 4 days with ciprofloxacin at 30 mg/kg of body weight twice a day cured cystitis and renal infection in noncatheterized mice. Similarly, ciprofloxacin reduced the bacterial burden to undetectable levels in catheterized mice but did not inhibit rebound of the infection upon cessation of antibiotic therapy. This methodology easily allows spatial information to be monitored sequentially throughout the entire disease process, including ascending UTI, treatment efficacy, and relapse, all without exogenous sampling, which is not possible with conventional methods.Urinary tract infections (UTI) are one of the most common bacterial infections in humans (9, 35). The majority of these infections follow instrumentation of the urinary tract, mainly urinary catheterization, with the development of catheter-associated bacteriuria being directly related to the duration of implant (6,18,37,44). Thus, it is commonplace for the incidence of bacteriuria to be as high as 95% in catheterized patients with implants present for 30 days or more (6, 44). Complications with such infections can lead to fever, cystitis, acute pyelonephritis, bacteremia, and death (44). Catheter-associated urinary tract infections are caused by a variety of uropathogens, including Escherichia coli, Klebsiella, Proteus, Enterococcus, Pseudomonas, Enterobacter, Serratia, and Candida (6,44).Typically, the bacterial biofilm growth on urinary catheter and adjacent mucosa accounts for the pathophysiology of catheter-associated UTI (25,26,31). Diseases involving bacterial biofilms are generally chronic and difficult to treat, be...

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Section: Discussionsupporting

confidence: 83%

Section: Methodsmentioning

confidence: 99%

Noninvasive Biophotonic Imaging for Monitoring of Catheter-Associated Urinary Tract Infections and Therapy in Mice

Kadurugamuwa¹,

Modi²,

Yu³

et al. 2005

Infect Immun

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“…Fukuoka et al reported the antibacterial activity of a new quinolone, T-3761 (13). This quinolone has a unique 1-aminocyclopropyl group at the C7 position (shown in Fig.…”

Section: Materuils and Methodsmentioning

confidence: 99%

“…This quinolone has a unique 1-aminocyclopropyl group at the C7 position (shown in Fig. 6), whose nature steers away from the traditional piperazine and pyrrolidine derivatives (13,29). The antibacterial activity of T-3761…”

Section: Materuils and Methodsmentioning

confidence: 99%

In vitro anti-Mycobacterium avium activities of quinolones: predicted active structures and mechanistic considerations

Klopman

Wang

et al. 1994

Antimicrob Agents Chemother

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The relationship between the structures of quinolones and their anti-Mycobacterium avium activities has been previously derived by using the Multiple Computer-Automated Structure Evaluation program. A number of substructural constraints required to overcome the resistance of most of the strains have been identified. Nineteen new quinolones which qualify under these substructural requirements were identified by the program and subsequently tested. The results show that the substructural attributes identified by the program produced a successful a priori prediction of the anti-M. avium activities of the new quinolones. All 19 quinolones were found to be active, and 4 of them are as active or better than ciprofloxacin. With these new quinolones, the updated multiple computer-automated structure evaluation program structure-activity relationship analysis has helped to uncover additional information about the nature of the substituents at the C5 and C7 positions needed for optimal inhibitory activity. A possible explanation of drug resistance based on the observation of suicide inactivation of bacterial cytochrome P-450 by the cyclopropylamine moiety has also been proposed and is discussed in this report. Furthermore, we confirm the view that the amount of the uncharged form present in a neutral pH solution plays a crucial role in the drug's penetration ability.Quinolones, more specifically, fluoroquinolones, have shown great potential in treating Mycobacterium avium-M intracellulare complex (MAI) infection, the most common bacterial infection complicating AIDS (6, 18). Although a large number of quinolone analogs have been made and their activities against some groups of bacteria, such as gram positive, gram negative, tuberculosis causing, etc., have been tested (36), only a limited number of quinolones have been tested for activity against MAI (25,42).To discover quinolones more potent against drug-resistant MAI organisms, we have previously tested 88 quinolones against a spectrum of M avium strains and identified relevant quantitative structure-activity relationships by Multiple Computer-Automated Structure Evaluation (MULTICASE) analysis (22, 23). From the activity spectrum of the 88 quinolones, we found variable and progressive resistance of the selected M avium strains. On the basis of susceptibility to quinolones, the strains used in our tests have been classified into a continuum between the most susceptible and the most resistant strains. In our previous analysis, we found that quinolones active against susceptible strains are not always active against resistant strains while those effective against resistant strains always exhibit good activities against susceptible strains. Furthermore, our previous studies have shown that as the susceptibility of the strains decreases, the identified substructures of quinolones required for the inhibitory activity become more restrictive. However, whether this progressive resistance is due to more selective penetration of the bacterial cell membrane or more restrictive bi...

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“…DU-6859a (DU) is a new fluoroquinolone antimicrobial agent with the chemical structure 7-[(7S)-7-amino-5-azaspiro [2,4]heptan-5-yl]-8-chloro-6-fluoro-1-[(lR,2S)-2-fluoro-1-cyclopropyl]-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid sesquihydrate (25). Since the presently available fluoroquinolone agents possess only moderate activities against many gram-positive bacteria, recent efforts have been directed toward the synthesis of compounds which have greater activities against these organisms, such as tosufloxacin (1), sparfloxacin (1,3,9), CI-934 (4), WIN 57273 (7,15,17), PD 117596 (5), PD 127391 (CI-960) (5,9,20), PD 131628 (9), T-3761 (10), OPC-17116 (14), AM-1155 (13), E-4497 (11), CP-74667 (16), and CP-99219 (6). DU appears to be one of the most active of these agents (25).…”

mentioning

confidence: 99%

Comparative in vitro activity of DU-6859a, a new fluoroquinolone agent, against gram-positive cocci

Korten¹,

Tomayko²,

Murray³

1994

Antimicrob Agents Chemother

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The in vitro activity of DU-6859a (DU), a new fluoroquinolone agent, was evaluated against 233 gram-positive cocci and was compared with those of ciprofloxacin, vancomycin, nafcillin, and ampicillin. The MICs of DU for 90% of the staphylococci tested were <0.06 ,ug/ml. All of the groups A and B and viridans group streptococci were inhibited by sO.125 ,ug of DU per ml, which was 32-fold more active than ciprofloxacin. On T-3761 (10), OPC-17116 (14), AM-1155 (13), E-4497 (11), CP-74667 (16), and CP-99219 (6). DU appears to be one of the most active of these agents (25). In the present study, the antibacterial activity of DU was investigated and compared with the activities of ciprofloxacin, vancomycin, nafcillin, and ampicillin against gram-positive cocci representing a broad range of antimicrobial resistance patterns. DU in powder form was provided by Daiichi Pharmaceutical Co., Tokyo, Japan; ciprofloxacin was provided by Miles Pharmaceuticals, West Haven, Conn.; and vancomycin, nafcillin, and ampicillin were purchased from Sigma Chemical Co., St. Louis, Mo. All staphylococci and streptococci were collected from hospitals in Houston, Tex., between 1989 and The bactericidal activity of DU against 7 E. faecalis and 3 E. faecium isolates was determined. Overnight cultures were diluted to yield a final inoculum of _107 CFU/ml in flasks containing brain heart infusion broth. The concentration of DU (2 ,ug/ml) used in the time-kill assays was recommended by the manufacturer to represent levels achievable in human serum. Samples (100 ,ul each) were withdrawn from flasks following 0, 4, and 24 h of incubation at 37°C with agitation. Undiluted and serially diluted samples were plated onto brain heart infusion agar plates. The lowest detectable number of organisms was 10 CFU/ml. The agar plates were incubated at 37°C for 24 h before CFU were counted. Bactericidal activity was defined as a reduction in CFU of >3 loglo. A drug carryover effect was excluded by showing that there was less than 5% difference in colony counts when 100 ,ul of 103 to 104 CFU/ml was plated onto antibiotic-free plates in the absence or presence of DU (2 ,ug/ml).The results of susceptibility testing with DU and a comparison of these results with the results of testing with other antibiotics are shown in Table 1. Fifty percent of the staphylococcal isolates tested were inhibited by .0.03 ,ug of DU per ml, and 90% were inhibited by .0.06 ,ug/ml (Table 1). The MICs for 90% of strains tested (MIC90s) were higher for the methicillin-resistant subgroups of S. aureus and coagulasenegative staphylococci than for the methicillin-susceptible sub-

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In vitro and in vivo antibacterial activities of T-3761, a new quinolone derivative

Cited by 48 publications

References 11 publications

Noninvasive Biophotonic Imaging for Monitoring of Catheter-Associated Urinary Tract Infections and Therapy in Mice

Noninvasive Biophotonic Imaging for Monitoring of Catheter-Associated Urinary Tract Infections and Therapy in Mice

In vitro anti-Mycobacterium avium activities of quinolones: predicted active structures and mechanistic considerations

Comparative in vitro activity of DU-6859a, a new fluoroquinolone agent, against gram-positive cocci

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