Pyrazolopyrimidines Establish MurC as a Vulnerable
Target in <i>Pseudomonas aeruginosa</i> and <i>Escherichia
coli</i>
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Abstract
The bacterial peptidoglycan biosynthesis
pathway provides multiple
targets for antibacterials, as proven by the clinical success of β-lactam
and glycopeptide classes of antibiotics. The Mur ligases play an essential
role in the biosynthesis of the peptidoglycan building block, <i>N</i>-acetyl-muramic acid-pentapeptide. MurC, the first of four
Mur ligases, ligates l-alanine to UDP-<i>N</i>-acetylmuramic
acid, initiating the synthesis of pentapeptide precursor. Therefore,
inhibiting the MurC enzyme should result in bacterial cell death.
Herein, we report a novel class of pyrazolopyrimidines with subnanomolar
potency against both <i>Escherichia coli</i> and <i>Pseudomonas aeruginosa</i> MurC enzymes, which demonstrates
a concomitant bactericidal activity against efflux-deficient strains.
Radio-labeled precursor incorporation showed these compounds selectively
inhibited peptidoglycan biosynthesis, and genetic studies confirmed
the target of pyrazolopyrimidines to be MurC. In the presence of permeability
enhancers such as colistin, pyrazolopyrimidines exhibited low micromolar
MIC against the wild-type bacteria, thereby, indicating permeability
and efflux as major challenges for this chemical series. Our studies
provide biochemical and genetic evidence to support the essentiality
of MurC and serve to validate the attractiveness of target for antibacterial
discovery