The 51st ICAAC Sep.17-20, 2011 - Chicago
 
Saturday, Sep 17, 2011, 11:30 AM - 1:30 PM  

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F1-141 - FSI-1686, a Novel β-Methylcarbapenem: Synthesis and Structure-Activity Relationships (SAR)    
D. Kim, H. Joo, E. Kowalik, S. Liu, Y. Li, S. Mao, M.hager, W. Choi 

Abstract: Background: Carbapenem such as Imipenem, Meropenem and Doripenem have been shown to have clinical utility against serious infections with Gram-negative bacteria. However, recently, there are a number of reports that have shown increasing drug-resistance rates on important pathogens. Especially, many reports have shown antimicrobial resistance is being serious problem against clinical isolates of Acinetobacter spp. The purpose of this investigation was a development of a new class carbapenem antibiotic against multi-drug resistant (MDR) pathogens while keeping potency against a broad range of G-(-) bacteria. Methods: MICs (Minimum Inhibitory Concentration) were determined by the serial agar dilution method which is recommended by NCCLS. Structure-activity relationships (SAR) were established by coupling a series of small molecules including Nitrogen-atom to the C-2 position of carbapenem. Results: The biological activity was depended greatly on the ending group at C-2 position of carbapenem. Azetidine, Pyrrolidine or acyclic amine derivatives were coupled. The basicity of nitrogen group was important to the potency against drug resistant bacteria, especially, Pseudomonas spp. The rigid compound was more active than the corresponding acyclic compound. When the hydrophilicity at the compound was increased, the potency was improved greatly. FSI-1686 was a well balanced compound on these physical properties and shown the excellent antibacterial activity against clinically isolated MDR-bacteria in comparison to the current clinical carbapenem. FSI-1686 had a 16-fold improved MIC90 against Acinetobacter baumannii (85 strains) and Pseudomonas aeruginosa (117 strains) compared to the Imipenem or Meropenem. Conclusions: FSI-1686, a new class carbapenem compound, was shown to be effective against various multi-drug resistant gram-negative bacteria including Acinetobacter baumannii.


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F1-142 - FSI-1686, a Novel β-Μethylcarbapenem; In Vitro Activity Against Carbapenem-Resistance Gram-Negative Bacteria     
H.Y. Joo, D.I. Kim, E. Kowalik, Y. Li, S. Mao, S. Liu, M. W. Hager, W.B. Choi

Abstract: Background: FSI-1686 is a new class of Carbapenem antibiotic which possesses excellent antibacterial activity against Multi-Drug Resistance (MDR) Gram-negative bacteria. The FSI-1686 was prepared and found to exhibit potent activity against Carbapenem-Resistance (CR) Acinetobacter baumannii and CR-Pseudomonas aeruginosa. Methods: MICs (Minimum Inhibitory Concentration) were determined by the serial agar or broth dilution methods which are recommended by CLSI. In this study we compared the activity of FSI-1686 with Imipenem, Doripenem, Ciprofloxacin, Colistin, Tigecycline and Tobramycin. Results: FSI-1686 has excellent potency (MIC90=4ug/ml) against Carbapenem-Resistance (CR) Acinetobacter baumannii. It has 16 times more active than Imipenem (MIC90=64ug/ml) and 8 times better than Doripenem (MIC90=32ug/ml). It was comparable to Colistin and Tigecycline. FSI-1686 was also highly active against Carbapenem-Resistance (CR) Pseudomonas aeruginosa (MIC90=4ug/ml).
Conclusions: The FIS-1686 is a new class of Carbapenem with potent activity against Carbapenem-Resistance (CR) A.baumannii and CR-P.aeruginosa. The FIS-1686 is a bactericidal antibiotic against CR-A.baumannii and CR-P.aeruginosa. The FSI-1686 is a potential carbapenem which is used for treatment of bacterial infections with multi-drug resistant gram-negative pathogens.


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F1-143 - Efficacy of FSI-1686 in Animal Model of Carbapenem-Resistance Gram-Negative Bacterial Infection
H.Y. Joo, D.I. Kim, E. Kowalik, Y. Li, S. Mao, S. Liu, M. W. Hager, W.B. Choi

Abstract
: Background: The in vivo efficacies of FSI-1686 and reference compounds were examined in murine septicemia and pulmonary infection mouse model caused by Carbapenem-Resistance (CR) Gram-negative bacteria. Methods: Systemic Infection induced intraperitonially in mice (4-5 weeks old, male, 18-21g) by a single inoculation of bacteria. FSI-1686, Meropenem, Doripenem, Colistin and Tigecycline were administered subcutaneously 5minute & 2 hour after bacterial challenge. The 50% protective dose (ED50, mg/kg) was calculated by Probit analysis method. Pulmonary Infection induced intranasally in neutropenic mice (5 weeks old, female, 20-23g) with Carbapenem-Resistance (CR) A.baumannii. FSI-1686, Meropenem, Doripenem, Colistin and Tigecycline were administered by subcutaneous injection twice daily for 3 days. Lungs of mice were removed aseptically, and viable bacterial counts were determined. Results: FSI-1686 has excellent potency against Carbapenem-Resistance (CR) Acinetobacter baumannii septicemia model. FSI-1686(ED50=0.35mg/kg) has 16 times better efficiency than Meropenem (ED50=5.87mg/kg) and was comparable to Colistin (ED50=0.35mg/kg). FSI-1686 (4.7 mg/kg) has 9 times better potency than Doripenem (42.9mg/kg) in CR-P.aeruginosa septicemia model. Efficacy of FSI-1686(ED50=9mg/kg) was more potent than Doripenem (ED50=18.1mg/kg) and Tigecycline (ED50=12.7mg/kg) in CR-K.pneumoniae septicemia model. In Pulmonary infection model, FSI-1686 has excellent efficacy against Carbapenem-Resistance (CR) Acinetobacter baumannii, and the efficacy of FSI-1686 was comparable to Tigecycline and significantly better than Meropenem. Conclusion: The FIS-1686 is highly effective in septicemia and Pulmonary infection mouse model against Carbapenem-Resistance (CR) Gram negative bacteria. The FSI-1686 is a potent carbapenem which is used for treatment of bacterial infections with multi-drug resistant gram-negative pathogens.