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 MIC90 values (MIC that inhibited 90% of the strains tested) of ≤2mg/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 >16mg/L and ≤0.5mg/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 300mg/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. [Copyright &y& Elsevier]