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1.
Antimicrob Agents Chemother ; 57(12): 5977-86, 2013 Dec.
Article in English | MEDLINE | ID: mdl-24041906

ABSTRACT

The type II topoisomerases DNA gyrase (GyrA/GyrB) and topoisomerase IV (ParC/ParE) are well-validated targets for antibacterial drug discovery. Because of their structural and functional homology, these enzymes are amenable to dual targeting by a single ligand. In this study, two novel benzothiazole ethyl urea-based small molecules, designated compound A and compound B, were evaluated for their biochemical, antibacterial, and pharmacokinetic properties. The two compounds inhibited the ATPase activity of GyrB and ParE with 50% inhibitory concentrations of <0.1 µg/ml. Prevention of DNA supercoiling by DNA gyrase was also observed. Both compounds potently inhibited the growth of a range of bacterial organisms, including staphylococci, streptococci, enterococci, Clostridium difficile, and selected Gram-negative respiratory pathogens. MIC90s against clinical isolates ranged from 0.015 µg/ml for Streptococcus pneumoniae to 0.25 µg/ml for Staphylococcus aureus. No cross-resistance with common drug resistance phenotypes was observed. In addition, no synergistic or antagonistic interactions between compound A or compound B and other antibiotics, including the topoisomerase inhibitors novobiocin and levofloxacin, were detected in checkerboard experiments. The frequencies of spontaneous resistance for S. aureus were <2.3 × 10(-10) with compound A and <5.8 × 10(-11) with compound B at concentrations equivalent to 8× the MICs. These values indicate a multitargeting mechanism of action. The pharmacokinetic properties of both compounds were profiled in rats. Following intravenous administration, compound B showed approximately 3-fold improvement over compound A in terms of both clearance and the area under the concentration-time curve. The measured oral bioavailability of compound B was 47.7%.


Subject(s)
Anti-Bacterial Agents/pharmacology , Bacterial Proteins/antagonists & inhibitors , Benzothiazoles/pharmacology , DNA Topoisomerase IV/antagonists & inhibitors , DNA Topoisomerases, Type II/metabolism , Gram-Negative Bacteria/drug effects , Gram-Positive Bacteria/drug effects , Topoisomerase Inhibitors/pharmacology , Urea/analogs & derivatives , Adenosine Triphosphatases/antagonists & inhibitors , Adenosine Triphosphatases/genetics , Adenosine Triphosphatases/metabolism , Animals , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacokinetics , Bacterial Proteins/genetics , Bacterial Proteins/metabolism , Benzothiazoles/chemistry , Benzothiazoles/pharmacokinetics , Cell Survival/drug effects , DNA Topoisomerase IV/genetics , DNA Topoisomerase IV/metabolism , DNA Topoisomerases, Type II/genetics , Escherichia coli/genetics , Escherichia coli/metabolism , Gene Expression , Gram-Negative Bacteria/enzymology , Gram-Negative Bacteria/growth & development , Gram-Positive Bacteria/enzymology , Gram-Positive Bacteria/growth & development , Hep G2 Cells , Humans , Interleukin-33 , Interleukins , Levofloxacin/pharmacology , Male , Microbial Sensitivity Tests , Novobiocin/pharmacology , Rats , Rats, Sprague-Dawley , Recombinant Proteins/genetics , Recombinant Proteins/metabolism , Topoisomerase Inhibitors/chemistry , Topoisomerase Inhibitors/pharmacokinetics , Urea/chemistry , Urea/pharmacokinetics , Urea/pharmacology
2.
Antimicrob Agents Chemother ; 57(1): 317-25, 2013 Jan.
Article in English | MEDLINE | ID: mdl-23114779

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.


Subject(s)
Anti-Bacterial Agents/pharmacokinetics , Bacterial Proteins/antagonists & inhibitors , Benzamides/pharmacokinetics , Cytoskeletal Proteins/antagonists & inhibitors , Methicillin-Resistant Staphylococcus aureus/drug effects , Oxazoles/pharmacokinetics , Prodrugs/pharmacokinetics , Staphylococcal Infections/drug therapy , Staphylococcus epidermidis/drug effects , Succinates/pharmacokinetics , Administration, Oral , Animals , Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/pharmacology , Bacterial Proteins/genetics , Benzamides/chemical synthesis , Benzamides/chemistry , Benzamides/pharmacology , Biological Availability , Colony Count, Microbial , Cytokinesis/drug effects , Cytoskeletal Proteins/genetics , Drug Resistance, Multiple, Bacterial , Female , Injections, Intravenous , Methicillin-Resistant Staphylococcus aureus/genetics , Methicillin-Resistant Staphylococcus aureus/growth & development , Mice , Microbial Sensitivity Tests , Mutation , Oxazoles/chemical synthesis , Oxazoles/pharmacology , Prodrugs/chemical synthesis , Prodrugs/pharmacology , Staphylococcal Infections/microbiology , Staphylococcus epidermidis/growth & development , Succinates/chemical synthesis , Succinates/pharmacology , Succinic Acid/chemistry , Thigh/microbiology , Treatment Outcome
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