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Antimicrob Agents Chemother. 2015 Aug;59(8):4845-55. doi: 10.1128/AAC.00708-15. Epub 2015 Jun 1.

TXA709, an FtsZ-Targeting Benzamide Prodrug with Improved Pharmacokinetics and Enhanced In Vivo Efficacy against Methicillin-Resistant Staphylococcus aureus.

Author information

1
Department of Pharmacology, Rutgers Robert Wood Johnson Medical School, Piscataway, New Jersey, USA.
2
TAXIS Pharmaceuticals, Inc., North Brunswick, New Jersey, USA Department of Medicinal Chemistry, Ernest Mario School of Pharmacy, Rutgers-The State University of New Jersey, Piscataway, New Jersey, USA.
3
TAXIS Pharmaceuticals, Inc., North Brunswick, New Jersey, USA.
4
St. John Hospital and Medical Center, Detroit, Michigan, USA.
5
St. John Hospital and Medical Center, Detroit, Michigan, USA Wayne State University School of Medicine, Detroit, Michigan, USA.
6
Department of Medicine (Infectious Disease), Rutgers Robert Wood Johnson Medical School, New Brunswick, New Jersey, USA Department of Pathology and Laboratory Medicine, Rutgers Robert Wood Johnson Medical School, New Brunswick, New Jersey, USA.
7
Department of Medicinal Chemistry, Ernest Mario School of Pharmacy, Rutgers-The State University of New Jersey, Piscataway, New Jersey, USA.
8
Department of Pharmacology, Rutgers Robert Wood Johnson Medical School, Piscataway, New Jersey, USA pilchds@rwjms.rutgers.edu.

Abstract

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 CF3 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.

PMID:
26033735
PMCID:
PMC4505295
DOI:
10.1128/AAC.00708-15
[Indexed for MEDLINE]
Free PMC Article

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