An Improved Small-Molecule Inhibitor of FtsZ with Superior In Vitro Potency, Drug-Like Properties and In Vivo Efficacy
By Lloyd Czaplewski, Nov 8 2012 02:24PM
Published in Antimicrobial Agents & Chemotherapy by Neil R. Stokes, Nicola Baker, James M. Bennett, Joanne Berry, Ian Collins, Lloyd G. Czaplewski, Alastair Logan, Rebecca Macdonald, Leanne MacLeod, Hilary Peasley, Jeffrey P. Mitchell, Narendra Nayal, Anju Yadav, Anil Srivastava and David J. Haydon
The bacterial cell division protein, FtsZ, is an attractive target for small-molecule antibacterial drug discovery. Derivatives of 3-methoxybenzamide, including compound PC190723, have previously been reported as potent and selective anti-staphylococcal agents, which exert their effect through the disruption of intracellular FtsZ function. Here, we report the further optimization of 3-methoxybenzamide derivatives towards a drug candidate. The in vitro and in vivo characterization of a more advanced lead compound, designated Compound 1, is described. Compound 1 was potently antibacterial, with an average MIC of 0.12 μg/mL against all staphylococcal species, including methicillin- and multidrug-resistant Staphylococcus aureus and S. epidermidis. Compound 1 inhibited a S. aureus strain carrying the G196A mutation in FtsZ, which confers resistance to PC190723. Like PC190723, Compound 1 acted on whole bacterial cells by blocking cytokinesis. No interactions between Compound 1 and a diverse panel of antibiotics were measured in checkerboard experiments. Compound 1 displayed suitable in vitro pharmaceutical properties and a favorable in vivo pharmacokinetic profile following intravenous and oral administration, with a calculated bioavailability of 82.0% in mice. Compound 1 demonstrated efficacy in the murine S. aureus systemic model of infection and caused a significant decrease in bacterial load in the thigh infection model. A greater reduction in the number of S. aureus cells recovered from infected thighs, equivalent to 3.68 log versus controls, was achieved using a succinate pro-drug of Compound 1, designated Compound 2. In summary, optimized derivatives of 3-methoxybenzamide may yield a first-in-class FtsZ inhibitor for the treatment of antibiotic-resistant staphylococcal infections.
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