TXA709, an FtsZ-Targeting Benzamide Prodrug with Improved Pharmacokinetics and Enhanced In Vivo Efficacy against Methicillin-Resistant Staphylococcus aureus
| Autor: | Yongzheng Zhang, Melvin P. Weinstein, Stephanie Saravolatz, Edmond J. LaVoie, Yi Lisa Lyu, Ajit K. Parhi, Joan Pawlak, Daniel S. Pilch, Louis D. Saravolatz, Malvika Kaul, Lilly Mark |
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| Rok vydání: | 2015 |
| Předmět: |
Methicillin-Resistant Staphylococcus aureus
Pyridines Microbial Sensitivity Tests Pharmacology medicine.disease_cause Methicillin Mice chemistry.chemical_compound Dogs Bacterial Proteins Daptomycin Pharmacokinetics Vancomycin In vivo medicine Animals Humans Prodrugs Pharmacology (medical) Cells Cultured Mice Inbred BALB C business.industry Linezolid Staphylococcal Infections Prodrug Methicillin-resistant Staphylococcus aureus Anti-Bacterial Agents Rats Cytoskeletal Proteins Thiazoles Infectious Diseases chemistry Staphylococcus aureus Benzamides Methicillin Resistance business Half-Life medicine.drug |
| Zdroj: | Antimicrobial Agents and Chemotherapy. 59:4845-4855 |
| ISSN: | 1098-6596 0066-4804 |
| DOI: | 10.1128/aac.00708-15 |
| Popis: | The clinical development of FtsZ-targeting benzamide compounds like PC190723 has been limited by poor drug-like and pharmacokinetic properties. Development of prodrugs of PC190723 (e.g., TXY541) resulted in enhanced pharmaceutical properties, which, in turn, led to improved intravenous efficacy as well as the first demonstration of oral efficacy in vivo against both methicillin-sensitive Staphylococcus aureus (MSSA) and methicillin-resistant S. aureus (MRSA). Despite being efficacious in vivo , TXY541 still suffered from suboptimal pharmacokinetics and the requirement of high efficacious doses. We describe here the design of a new prodrug (TXA709) in which the Cl group on the pyridyl ring has been replaced with a CF 3 functionality that is resistant to metabolic attack. As a result of this enhanced metabolic stability, the product of the TXA709 prodrug (TXA707) is associated with improved pharmacokinetic properties (a 6.5-fold-longer half-life and a 3-fold-greater oral bioavailability) and superior in vivo antistaphylococcal efficacy relative to PC190723. We validate FtsZ as the antibacterial target of TXA707 and demonstrate that the compound retains potent bactericidal activity against S. aureus strains resistant to the current standard-of-care drugs vancomycin, daptomycin, and linezolid. These collective properties, coupled with minimal observed toxicity to mammalian cells, establish the prodrug TXA709 as an antistaphylococcal agent worthy of clinical development. |
| Databáze: | OpenAIRE |
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