期刊
INTERNATIONAL JOURNAL OF ANTIMICROBIAL AGENTS
卷 41, 期 4, 页码 363-371出版社
ELSEVIER SCIENCE BV
DOI: 10.1016/j.ijantimicag.2012.12.001
关键词
Mode of action; DNA topology; Topoisomerase inhibition
资金
- Infection Innovative Medicines Unit of AstraZeneca (Waltham, MA)
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 MIC90 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 MIC90 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. (C) 2012 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved.
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