Exploring the positional attachment of glycopeptide/beta-lactam heterodimers
| Autor: | Sharath S. Hegde, Matthew B. Nodwell, Martin S. Linsell, Kevin M. Krause, Paul R. Fatheree, Daniel Marquess, David W. Green, John L. Pace, James B. Aggen, Koné Kaniga, Sean G. Trapp, Jason P. Chinn, Seok-Ki Choi, J. Kevin Judice, Burton G. Christensen, Michael R. Leadbetter, S. Derek Turner, Daniel D. Long, Edmund J. Moran |
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| Rok vydání: | 2009 |
| Předmět: |
Methicillin-Resistant Staphylococcus aureus
Magnetic Resonance Spectroscopy medicine.drug_class Cephalosporin Antibiotics Microbial Sensitivity Tests medicine.disease_cause Gram-Positive Bacteria beta-Lactams Microbiology chemistry.chemical_compound Mice In vivo Drug Discovery medicine Animals Pharmacology Molecular Structure Chemistry Glycopeptides biochemical phenomena metabolism and nutrition Methicillin-resistant Staphylococcus aureus Glycopeptide Anti-Bacterial Agents Cephalosporins Staphylococcus aureus Drug Design Lactam Vancomycin Female Dimerization medicine.drug |
| Zdroj: | The Journal of antibiotics. 61(10) |
| ISSN: | 0021-8820 |
| Popis: | Further investigations towards novel glycopeptide/beta-lactam heterodimers are reported. Employing a multivalent approach to drug discovery, vancomycin and cephalosporin synthons, 4, 2, 5 and 10, 18, 25 respectively, were chemically linked to yield heterodimer antibiotics. These novel compounds were designed to inhibit Gram-positive bacterial cell wall biosynthesis by simultaneously targeting the principal cellular targets of both glycopeptides and beta-lactams. The positional attachment of both the vancomycin and the cephalosporin central cores has been explored and the SAR is reported. This novel class of bifunctional antibiotics 28-36 all displayed remarkable potency against a wide range of Gram-positive organisms, including methicillin-resistant Staphylococcus aureus (MRSA). A subset of compounds, 29, 31 and 35 demonstrated excellent bactericidal activity against MRSA (ATCC 33591) and 31 and 35 also exhibited superb in vivo efficacy in a mouse model of MRSA infection. As a result of this work compound 35 was selected as a clinical candidate, TD-1792. |
| Databáze: | OpenAIRE |
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