6-Arylpyrido[2,3-d]pyrimidines as novel ATP-competitive inhibitors of bacterial D-alanine:D-alanine ligase.

6-Arylpyrido[2,3-d]pyrimidines as novel ATP-competitive inhibitors of bacterial D-alanine:D-alanine ligase.

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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 Cartoon Art 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/PRINCIPAL FINDINGS: Encouraged by recent successful attempts to find selective ATP-competitive inhibitors of bacterial enzymes we designed, synthesized and evaluated a server library of 6-arylpyrido[2,3-d]pyrimidine-based compounds as inhibitors of Escherichia coli 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 binding to the ATP-binding site was additionally studied with docking.

Some of these inhibitors were found to possess antibacterial activity against membrane-compromised and efflux pump-deficient strains of E.coli.CONCLUSIONS/SIGNIFICANCE: We discovered new ATP-competitive inhibitors of DdlB, which may serve as a starting point for development of more potent inhibitors of DdlB that could include both, an ATP-competitive and D-Ala competitive moiety.