title: An improved small-molecule inhibitor of FtsZ with superior in vitro potency, drug-like properties, and in vivo efficacy.
abstract: The bacterial cell division protein FtsZ is an attractive target for small-molecule antibacterial drug discovery. Derivatives of 3-methoxybenzamide, including compound PC190723, have been reported to be potent and selective antistaphylococcal agents which exert their effects 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 Staphylococcus epidermidis. Compound 1 inhibited an 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 a murine model of systemic S. aureus infection and caused a significant decrease in the 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 units, than in those recovered from controls was achieved using a succinate prodrug of compound 1, which was 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.
authors.affiliation: Biota Europe Ltd., Begbroke Science Park, Oxfordshire, United Kingdom. n.stokes@biota.com.au
authors.forename: Neil R
authors.initials: NR
authors.lastname: Stokes
authors.forename: Nicola
authors.initials: N
authors.lastname: Baker
authors.forename: James M
authors.initials: JM
authors.lastname: Bennett
authors.forename: Joanne
authors.initials: J
authors.lastname: Berry
authors.forename: Ian
authors.initials: I
authors.lastname: Collins
authors.forename: Lloyd G
authors.initials: LG
authors.lastname: Czaplewski
authors.forename: Alastair
authors.initials: A
authors.lastname: Logan
authors.forename: Rebecca
authors.initials: R
authors.lastname: Macdonald
authors.forename: Leanne
authors.initials: L
authors.lastname: Macleod
authors.forename: Hilary
authors.initials: H
authors.lastname: Peasley
authors.forename: Jeffrey P
authors.initials: JP
authors.lastname: Mitchell
authors.forename: Narendra
authors.initials: N
authors.lastname: Nayal
authors.forename: Anju
authors.initials: A
authors.lastname: Yadav
authors.forename: Anil
authors.initials: A
authors.lastname: Srivastava
authors.forename: David J
authors.initials: DJ
authors.lastname: Haydon
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000493:pharmacokinetics* / Q000494:pharmacology; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics; D001549:Benzamides / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology; D001682:Biological Availability; D015169:Colony Count, Microbial; D048749:Cytokinesis / Q000187:drug effects; D003598:Cytoskeletal Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics; D024901:Drug Resistance, Multiple, Bacterial; D005260:Female; D007275:Injections, Intravenous; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects* / Q000235:genetics / Q000254:growth & development; D051379:Mice; D008826:Microbial Sensitivity Tests; D009154:Mutation; D010080:Oxazoles / Q000138:chemical synthesis / Q000493:pharmacokinetics* / Q000494:pharmacology; D011355:Prodrugs / Q000138:chemical synthesis / Q000493:pharmacokinetics* / Q000494:pharmacology; D013203:Staphylococcal Infections / Q000188:drug therapy* / Q000382:microbiology; D013212:Staphylococcus epidermidis / Q000187:drug effects* / Q000254:growth & development; D013386:Succinates / Q000138:chemical synthesis / Q000493:pharmacokinetics* / Q000494:pharmacology; D019802:Succinic Acid / Q000737:chemistry; D013848:Thigh / Q000382:microbiology; D016896:Treatment Outcome
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D001549:Benzamides; D003598:Cytoskeletal Proteins; C071525:FtsZ protein, Bacteria; D010080:Oxazoles; D011355:Prodrugs; D013386:Succinates; D019802:Succinic Acid; C025159:3-methoxybenzamide