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The Mur ligases play an essential role in the biosynthesis of bacterial peptidoglycan and hence are attractive antibacterial targets. A screen of the AstraZeneca compound library led to the identification of compound A, a pyrazolopyrimidine, as a potent inhibitor ofEscherichia coli andPseudomonas aeruginosa MurC. However, cellular activity againstE. coli orP. aeruginosa was not observed. Compound A was active against efflux pump mutants of both strains. Experiments using anE. coli tolC mutant revealed accumulation of the MurC substrate and a decrease in the level of product upon treatment with compound A, indicating inhibition of MurC enzyme in these cells. Such a modulation was not observed in theE. coli wild-type cells. Further, overexpression of MurC in theE. coli tolC mutant led to an increase in the compound A MIC by ≥16-fold, establishing a correlation between MurC inhibition and cellular activity. In addition, estimation of the intracellular compound A level showed an accumulation of the compound over time in thetolC mutant strain. A significant compound A level was not detected in the wild-typeE. coli strain even upon treatment with high concentrations of the compound. Therefore, the lack of MIC and absence of MurC inhibition in wild-typeE. coli were possibly due to suboptimal compound concentration as a consequence of a high efflux level and/or poor permeativity of compound A.

UDP- N -Acetylmuramic Acid l -Alanine Ligase (MurC) Inhibition in a tolC Mutant Escherichia coli Strain Leads to Cell Death