title: TXA709, an FtsZ-Targeting Benzamide Prodrug with Improved Pharmacokinetics and Enhanced In Vivo Efficacy against Methicillin-Resistant Staphylococcus aureus.
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.
authors.affiliation: Department of Pharmacology, Rutgers Robert Wood Johnson Medical School, Piscataway, New Jersey, USA.
authors.forename: Malvika
authors.initials: M
authors.lastname: Kaul
authors.affiliation: 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.
authors.forename: Lilly
authors.initials: L
authors.lastname: Mark
authors.affiliation: TAXIS Pharmaceuticals, Inc., North Brunswick, New Jersey, USA.
authors.forename: Yongzheng
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: 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.
authors.forename: Ajit K
authors.initials: AK
authors.lastname: Parhi
authors.affiliation: Department of Pharmacology, Rutgers Robert Wood Johnson Medical School, Piscataway, New Jersey, USA.
authors.forename: Yi Lisa
authors.initials: YL
authors.lastname: Lyu
authors.affiliation: St. John Hospital and Medical Center, Detroit, Michigan, USA.
authors.forename: Joan
authors.initials: J
authors.lastname: Pawlak
authors.affiliation: St. John Hospital and Medical Center, Detroit, Michigan, USA.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Saravolatz
authors.affiliation: St. John Hospital and Medical Center, Detroit, Michigan, USA Wayne State University School of Medicine, Detroit, Michigan, USA.
authors.forename: Louis D
authors.initials: LD
authors.lastname: Saravolatz
authors.affiliation: 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.
authors.forename: Melvin P
authors.initials: MP
authors.lastname: Weinstein
authors.affiliation: Department of Medicinal Chemistry, Ernest Mario School of Pharmacy, Rutgers-The State University of New Jersey, Piscataway, New Jersey, USA.
authors.forename: Edmond J
authors.initials: EJ
authors.lastname: LaVoie
authors.affiliation: Department of Pharmacology, Rutgers Robert Wood Johnson Medical School, Piscataway, New Jersey, USA pilchds@rwjms.rutgers.edu.
authors.forename: Daniel S
authors.initials: DS
authors.lastname: Pilch
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000493:pharmacokinetics / Q000494:pharmacology; D001426:Bacterial Proteins / Q000378:metabolism*; D001549:Benzamides / Q000493:pharmacokinetics* / Q000494:pharmacology*; D002478:Cells, Cultured; D003598:Cytoskeletal Proteins / Q000378:metabolism*; D017576:Daptomycin / Q000494:pharmacology; D004285:Dogs; D006207:Half-Life; D006801:Humans; D000069349:Linezolid / Q000494:pharmacology; D008712:Methicillin / Q000494:pharmacology; D016106:Methicillin Resistance / Q000187:drug effects*; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008826:Microbial Sensitivity Tests / Q000379:methods; D011355:Prodrugs / Q000493:pharmacokinetics* / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D013203:Staphylococcal Infections / Q000188:drug therapy; D013844:Thiazoles / Q000494:pharmacology; D014640:Vancomycin / Q000494:pharmacology
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D001549:Benzamides; D003598:Cytoskeletal Proteins; C071525:FtsZ protein, Bacteria; C531944:PC190723; D011355:Prodrugs; D011725:Pyridines; D013844:Thiazoles; D014640:Vancomycin; C037689:benzamide; D000069349:Linezolid; D017576:Daptomycin; D008712:Methicillin