In Vivo Pharmacodynamic Evaluation of an FtsZ Inhibitor, TXA-709, and Its Active Metabolite, TXA-707, in a Murine Neutropenic Thigh Infection Model

Abstract

Antibiotics with novel mechanisms of action are urgently needed. Processes of cellular division are attractive targets for new drug development. FtsZ, an integral protein involved in cell cytokinesis, is a representative example. In the present study, the pharmacodynamic (PD) activity of an FtsZ inhibitor, TXA-709, and its active metabolite, TXA-707, was evaluated in the neutropenic murine thigh infection model against 5 Staphylococcus aureus isolates, including both methicillin-susceptible and methicillin-resistant isolates. The pharmacokinetics (PK) of the TXA-707 active metabolite were examined after oral administration of the TXA-709 prodrug at 10, 40, and 160 mg/kg of body weight. The half-life ranged from 3.2 to 4.4 h, and the area under the concentration-time curve (AUC) and maximum concentration of drug in serum (C max ) were relatively linear over the doses studied. Methicillin-resistant Staphylococcal aureus (MRSA) infections are a major public health threat (1). In the United States, S. aureus is the most common cause of nosocomial infection and leads to more than 80 thousand illnesses and 11 thousand deaths yearly (2). Ambulatory visits for cases of skin and soft tissue infection (SSTI) continue to increase in number and amounted to more than 14 million in a 2005 survey (3). Methicillin-resistant S. aureus infections account for a disproportionate rise in the incidence of those cases and in the need for hospitalization and unfortunately have limited therapeutic options (3-6). Novel antimicrobial agents that target cellular functions distinctly different from those targeted by current therapies and that show activity against drug-resistant isolates are urgently needed (7-10). Bacterial cell division represents an attractive area for antibiotic research to meet these needs.FtsZ is a major functional protein involved in cell division through formation of a Z-ring polymeric structure of FtsZ subunits (11-13). Disruption of this process leads to inhibition of cell division and eventual cell death (14). In addition to its novel mechanism of action, FtsZ is an attractive drug target because it is highly conserved in bacteria but absent in eukaryotic cells.We describe a pharmacodynamic (PK) evaluation of a methoxybenzamide FtsZ inhibitor, TXA-709, and its active metabolite, TXA-707, in a murine neutropenic thigh infection model against S. aureus. The impact of dose and dosing regimen on the in vivo efficacy of this drug was assessed. Specifically, the studies included were designed to (i) determine the pharmacokinetic/ pharmacodynamic (PK/PD) index (peak serum level divided by the MIC [C max /MIC], area under the concentration-time curve over 24 h in the steady state divided by the MIC [AUC/MIC ratio], or duration of time serum levels exceed the MIC [time above MIC]) associated with optimal drug efficacy and (ii) identify the magnitude of the PK/PD index value required for efficacy among multiple S. aureus isolates, including those with beta-lactam resistance. MATERIALS AND METHODSOrganisms, media, and anti...

2,6‐Difluorobenzamide Inhibitors of Bacterial Cell Division Protein FtsZ: Design, Synthesis, and Structure–Activity Relationships

“…Consequently, a new prodrug (TXA709, Figure ) of a different FtsZ‐targeting benzamide compound (TXA707, Figure ) arose in recent years and proved to have metabolic stability, good pharmacokinetic properties, and high in vivo potency versus MRSA . In addition, combination of TXA709 with cefdinir was demonstrated to be effective and synergistic …”

Efficient Synthesis of Amine-Linked 2,4,6-Trisubstituted Pyrimidines as a New Class of Bacterial FtsZ Inhibitors

“…Some exhibit potent antibacterial activity with minimum inhibitory concentration (MIC) at the micromolar range. PC190723 (Figure , top left) − and its prodrugs 1a , 1b , − and benzamide 2 have been demonstrated to exhibit in vitro and in vivo efficacy in a murine infection model. Moreover, X-ray crystallographic analysis revealed that PC190723 binds to a narrow cleft formed by the H7, T7 loop, and C-terminal β sheet (Figure , black oval) .…”

β-Lactams against the Fortress of the Gram-Positive Staphylococcus aureus Bacterium

“…Combination of 22 with imipenem markedly reduced (by 10×) the frequency of resistance mutation to 22 . The mechanism of 22 is stabilization of the FtsZ structure resulting in a deformed Z-ring. − As a consequence of the poor solubility (and lack of oral availability) of 22 , , extensive efforts were made toward the optimization (both as structures and as prodrugs) of the PC190723 class . Among the former are the benzodioxane-containing structure ( 23 ), the more potent PC190723-derived structure 24 , and the imide pro-drug 25 of a second PC190723-derived structure (the active metabolite is TXA-707, structure 26 ) .…”

“…The mechanism of 22 is stabilization of the FtsZ structure resulting in a deformed Z-ring. − As a consequence of the poor solubility (and lack of oral availability) of 22 , , extensive efforts were made toward the optimization (both as structures and as prodrugs) of the PC190723 class . Among the former are the benzodioxane-containing structure ( 23 ), the more potent PC190723-derived structure 24 , and the imide pro-drug 25 of a second PC190723-derived structure (the active metabolite is TXA-707, structure 26 ) . Pairing of 26 with each β-lactam within a panel of clinically used β-lactams confirmed a synergistic interaction and further showed that the β-lactams that gave the best synergy targeted preferentially S. aureus PBP2 (imipenem and cefnidir). , Prodrug 25 (structure code TXA709) completed a phase 1 clinical trial .…”