title: Novel topoisomerase inhibitors: microbiological characterisation and in vivo efficacy of pyrimidines.
abstract: Pyrimidine compounds were identified as inhibitors of DNA topoisomerase IV through high-throughput screening. This study was designed to exemplify the in vitro activity of the pyrimidines against Gram-positive and Gram-negative microorganisms, to reveal the mode of action of these compounds and to demonstrate their in vivo efficacy. Frequencies of resistance to pyrimidines among Staphylococcus aureus and Streptococcus pneumoniae were <10(-10) at four times their minimum inhibitory concentrations (MICs). These compounds exhibited a dual mode of action through inhibition of the ParE subunit of DNA topoisomerase IV as well as the GyrB subunit of DNA gyrase, a homologue of DNA topoisomerase IV. Pyrimidines were shown to have MIC(90) values (MIC that inhibited 90% of the strains tested) of ≤2 mg/L against Gram-positive pathogens, including meticillin-resistant S. aureus, quinolone- and meticillin-resistant S. aureus, vancomycin-resistant enterococci, penicillin-non-susceptible S. pneumoniae and Streptococcus pyogenes, and MIC(90) values of 2- to >16 mg/L and ≤0.5 mg/L against the Gram-negative pathogens Haemophilus influenzae and Moraxella catarrhalis, respectively. The pyrimidines were bactericidal and exhibited a ca. 1000-fold reduction of the bacterial counts at 300 mg/kg in a S. pneumoniae lung infection model. The microbiological properties and in vivo efficacy of pyrimidines underscore their potential as candidates for the treatment of soft-tissue infections and hospital-acquired pneumonia.
authors.affiliation: AstraZeneca R&D, Infection iMED, 35 Gatehouse Drive, Waltham, MA 02451, USA. maria.urianickelsen@gmail.com
authors.forename: Maria
authors.initials: M
authors.lastname: Uria-Nickelsen
authors.forename: Georg
authors.initials: G
authors.lastname: Neckermann
authors.forename: Shubha
authors.initials: S
authors.lastname: Sriram
authors.forename: Beth
authors.initials: B
authors.lastname: Andrews
authors.forename: John I
authors.initials: JI
authors.lastname: Manchester
authors.forename: Dan
authors.initials: D
authors.lastname: Carcanague
authors.forename: Suzanne
authors.initials: S
authors.lastname: Stokes
authors.forename: Kenneth G
authors.initials: KG
authors.lastname: Hull
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use*; D027101:DNA Topoisomerase IV / Q000037:antagonists & inhibitors* / Q000737:chemistry; D004195:Disease Models, Animal; D005260:Female; D006090:Gram-Negative Bacteria / Q000187:drug effects*; D006095:Gram-Positive Cocci / Q000187:drug effects*; D006801:Humans; D051379:Mice; D008826:Microbial Sensitivity Tests / Q000592:standards; D008958:Models, Molecular; D011018:Pneumonia, Pneumococcal / Q000188:drug therapy* / Q000382:microbiology; D013296:Streptococcus pneumoniae / Q000187:drug effects; D059005:Topoisomerase II Inhibitors; D059003:Topoisomerase Inhibitors / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use*; D016896:Treatment Outcome
chemical_list: D000900:Anti-Bacterial Agents; D059005:Topoisomerase II Inhibitors; D059003:Topoisomerase Inhibitors; D027101:DNA Topoisomerase IV