Novel Bacterial Acetyl Coenzyme A Carboxylase Inhibitors with Antibiotic Efficacy In Vivo
| العنوان: | Novel Bacterial Acetyl Coenzyme A Carboxylase Inhibitors with Antibiotic Efficacy In Vivo |
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| المؤلفون: | Thomas Lampe, Ben Dr. Newton, Rainer Endermann, Christoph Freiberg, Joachim Schuhmacher, Karl Ziegelbauer, Jens Pohlmann, P. G. Nell, Dieter Habich, Michael Dr. Otteneder |
| المصدر: | Antimicrobial Agents and Chemotherapy. 50:2707-2712 |
| بيانات النشر: | American Society for Microbiology, 2006. |
| سنة النشر: | 2006 |
| مصطلحات موضوعية: | Male, Staphylococcus aureus, medicine.drug_class, Coenzyme A, Gram-positive bacteria, Molecular Sequence Data, Antibiotics, Colony Count, Microbial, Mice, Inbred Strains, Microbial Sensitivity Tests, In Vitro Techniques, Biology, Gram-Positive Bacteria, Mice, Structure-Activity Relationship, chemistry.chemical_compound, Anti-Infective Agents, In vivo, Sepsis, Acetamides, medicine, Animals, Humans, Structure–activity relationship, Potency, Pharmacology (medical), Amino Acid Sequence, Enzyme Inhibitors, Rats, Wistar, Mechanisms of Action: Physiological Effects, Oxazolidinones, Antibacterial agent, Pharmacology, Linezolid, Acetyl-CoA carboxylase, Water, biology.organism_classification, Amides, Survival Analysis, Anti-Bacterial Agents, Rats, Disease Models, Animal, Infectious Diseases, Amino Acid Substitution, Solubility, Biochemistry, chemistry, Female, Acetyl-CoA Carboxylase |
| الوصف: | The pseudopeptide pyrrolidinedione antibiotics, such as moiramide B, have recently been discovered to target the multisubunit acetyl coenzyme A (acetyl-CoA) carboxylases of bacteria. In this paper, we describe synthetic variations of each moiety of the modularly composed pyrrolidinediones, providing insight into structure-activity relationships of biochemical target activity, in vitro potency, and in vivo efficacy. The novel derivatives showed highly improved activities against gram-positive bacteria compared to those of previously reported variants. The compounds exhibited a MIC 90 value of 0.1 μg/ml against a broad spectrum of Staphylococcus aureus clinical isolates. No cross-resistance to antibiotics currently used in clinical practice was observed. Resistance mutations induced by pyrrolidinediones are exclusively located in the carboxyltransferase subunits of the bacterial acetyl-CoA carboxylase, indicating the identical mechanisms of action of all derivatives tested. Improvement of the physicochemical profile was achieved by salt formation, leading to aqueous solubilities of up to 5 g/liter. For the first time, the in vitro activity of this compound class was compared with its in vivo efficacy, demonstrating a path from compounds weakly active in vivo to agents with significant efficacy. In a murine model of S. aureus sepsis, the 100% effective dose of the best compound reported was 25 mg/kg of body weight, only fourfold higher than that of the comparator molecule linezolid. The obvious improvements achieved by chemical derivatization reflect the potential of this novel antibiotic compound class for future therapy. |
| تدمد: | 1098-6596 0066-4804 |
| DOI: | 10.1128/aac.00012-06 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::1fbc28d4340e67ee78e624770de04a1e https://doi.org/10.1128/aac.00012-06 |
| Rights: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....1fbc28d4340e67ee78e624770de04a1e |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 10986596 00664804 |
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| DOI: | 10.1128/aac.00012-06 |