ABSTRACT
3-Methoxybenzamide is a weak inhibitor of the essential bacterial cell division protein FtsZ. Exploration of the structure-activity relationships of 3-methoxybenzamide analogues led to the identification of potent anti-staphylococcal compounds.
Subject(s)
Anti-Bacterial Agents/pharmacology , Bacterial Proteins/antagonists & inhibitors , Benzamides/pharmacology , Cytoskeletal Proteins/antagonists & inhibitors , Staphylococcus/drug effects , Anti-Bacterial Agents/chemistry , Benzamides/chemistry , Microbial Sensitivity Tests , Structure-Activity RelationshipABSTRACT
FtsZ is an essential bacterial guanosine triphosphatase and homolog of mammalian beta-tubulin that polymerizes and assembles into a ring to initiate cell division. We have created a class of small synthetic antibacterials, exemplified by PC190723, which inhibits FtsZ and prevents cell division. PC190723 has potent and selective in vitro bactericidal activity against staphylococci, including methicillin- and multi-drug-resistant Staphylococcus aureus. The putative inhibitor-binding site of PC190723 was mapped to a region of FtsZ that is analogous to the Taxol-binding site of tubulin. PC190723 was efficacious in an in vivo model of infection, curing mice infected with a lethal dose of S. aureus. The data validate FtsZ as a target for antibacterial intervention and identify PC190723 as suitable for optimization into a new anti-staphylococcal therapy.
Subject(s)
Anti-Bacterial Agents/pharmacology , Bacillus subtilis/drug effects , Bacterial Proteins/antagonists & inhibitors , Cytoskeletal Proteins/antagonists & inhibitors , Pyridines/pharmacology , Staphylococcal Infections/drug therapy , Staphylococcus aureus/drug effects , Thiazoles/pharmacology , Amino Acid Sequence , Animals , Anti-Bacterial Agents/therapeutic use , Bacillus subtilis/chemistry , Bacillus subtilis/genetics , Bacterial Proteins/chemistry , Bacterial Proteins/genetics , Bacterial Proteins/metabolism , Binding Sites , Cell Division/drug effects , Crystallography, X-Ray , Cytoskeletal Proteins/chemistry , Cytoskeletal Proteins/genetics , Cytoskeletal Proteins/metabolism , Drug Resistance, Bacterial/genetics , Drug Resistance, Multiple, Bacterial , Ligands , Methicillin Resistance , Mice , Microbial Sensitivity Tests , Models, Molecular , Molecular Sequence Data , Mutation , Protein Conformation , Pyridines/chemistry , Pyridines/metabolism , Pyridines/therapeutic use , Staphylococcus aureus/chemistry , Thiazoles/chemistry , Thiazoles/metabolism , Thiazoles/therapeutic use , Tubulin/chemistry , Tubulin/metabolismABSTRACT
The Burkholderia cepacia complex comprises a group of nine closely related species that have emerged as life-threatening pulmonary pathogens in immunocompromised patients, particularly individuals with cystic fibrosis or chronic granulomatous disease. Attempts to explain the genomic plasticity, adaptability and virulence of the complex have paid little attention to bacteriophages, particularly the potential contribution of lysogenic conversion and transduction. In this study, lysogeny was observed in 10 of 20 representative strains of the B. cepacia complex. Three temperate phages and five lytic phages isolated from soils, river sediments or the plant rhizosphere were chosen for further study. Six phages exhibited T-even morphology and two were lambda-like. The host range of individual phages, when tested against 66 strains of the B. cepacia complex and a representative panel of other pseudomonads, was not species-specific within the B. cepacia complex and, in some phages, included Burkholderia gladioli and Pseudomonas aeruginosa. These new data indicate a potential role for phages of the B. cepacia complex in the evolution of these soil bacteria as pathogens of plants, humans and animals, and as novel therapeutic agents.
