UDP- N -Acetylmuramic Acid l -Alanine Ligase (MurC) Inhibition in a tolC Mutant Escherichia coli Strain Leads to Cell Death
| Autor: | Sreevalli Sharma, Monalisa Chatterji, Ashwini Narayan, Sudha Ravishankar, Vasanthi Ramachandran, Vaishali Humnabadkar, Supreeth Guptha, Shahul Hameed, Praveena Manjrekar, Murugan Chinnapattu, K.R. Prabhakar |
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| Rok vydání: | 2014 |
| Předmět: |
Mutant
Biology medicine.disease_cause chemistry.chemical_compound Biosynthesis Escherichia coli medicine Pharmacology (medical) Peptide Synthases Mechanisms of Action: Physiological Effects Pharmacology chemistry.chemical_classification Alanine DNA ligase Escherichia coli Proteins Membrane Transport Proteins Uridine Diphosphate N-Acetylmuramic Acid Infectious Diseases Enzyme chemistry Biochemistry Mutation Pseudomonas aeruginosa Peptidoglycan Efflux Bacterial Outer Membrane Proteins |
| Zdroj: | Antimicrobial Agents and Chemotherapy. 58:6165-6171 |
| ISSN: | 1098-6596 0066-4804 |
| Popis: | 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 of Escherichia coli and Pseudomonas aeruginosa MurC. However, cellular activity against E. coli or P. aeruginosa was not observed. Compound A was active against efflux pump mutants of both strains. Experiments using an E. 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 the E. coli wild-type cells. Further, overexpression of MurC in the E. 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 the tolC mutant strain. A significant compound A level was not detected in the wild-type E. coli strain even upon treatment with high concentrations of the compound. Therefore, the lack of MIC and absence of MurC inhibition in wild-type E. coli were possibly due to suboptimal compound concentration as a consequence of a high efflux level and/or poor permeativity of compound A. |
| Databáze: | OpenAIRE |
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