6-Arylpyrido[2,3-d]pyrimidines as Novel ATP-Competitive Inhibitors of Bacterial D-AlanineD-Alanine Ligase 英文参考文献.docVIP

6-Arylpyrido[2,3-d]pyrimidinesasNovelATP- CompetitiveInhibitorsofBacterialD-Alanine:D-Alanine Ligase VeronikaSkedeljˇ 1,EmilijaArsovska1,TihomirTomasˇic′1,AnaKroflicˇ2,VesnaHodnik3,MartinaHrast1, MarijaBesˇter-Rogacˇ2,GregorAnderluh3,StanislavGobec1,JulieanneBostock4,IanChopra4, AlexJ.O’Neill4,ChristopherRandall4,AnamarijaZega1* 1 Faculty of Pharmacy, University of Ljubljana, Ljubljana, Slovenia, 2 Faculty of Chemistry and Chemical Technology, University of Ljubljana, Ljubljana, Slovenia, 3 Biotechnical faculty, Infrastructural Center for Surface Plasmon Resonance, University of Ljubljana, Ljubljana, Slovenia,4 Antimicrobial Research Centre and Instititue of Molecular Cellular Biology, University of Leeds, Leeds, United Kingdom Abstract Background: ATP-dependent D-alanine:D-alanine ligase (Ddl) is a part of biochemical machinery involved in peptidoglycan biosynthesis, as it catalyzes the formation of the terminal D-ala-D-ala dipeptide of the peptidoglycan precursor UDPMurNAc- pentapeptide. Inhibition of Ddl prevents bacterial growth, which makes this enzyme an attractive and viable target in the urgent search of novel effective antimicrobial drugs. To address the problem of a relentless increase in resistance to known antimicrobial agents we focused our attention to discovery of novel ATP-competitive inhibitors of Ddl. Methodology/PrincipalFindings: Encouraged by recent successful attempts to find selective ATP-competitive inhibitors of bacterial enzymes we designed, synthesized and evaluated a library of 6-arylpyrido[2,3-d]pyrimidine-based compounds as inhibitors ofEscherichiacoli DdlB. Inhibitor binding to the target enzyme was subsequently confirmed by surface plasmon resonance and studied with isothermal titration calorimetry. Since kinetic analysis indicated that 6-arylpyrido[2,3- d]pyrimidines compete with the enzyme substrate ATP, inhibitor b