Inhibition of tRNA-dependent ligase MurM from Streptococcus pneumoniae by phosphonate and sulfonamide inhibitors
| Autor: | Elena Cressina, Timothy D. H. Bugg, B. James Mok, David I. Roper, Christopher G. Dowson, Gianfranco De Pascale, Adrian J. Lloyd, Stephen Caddick |
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| Rok vydání: | 2008 |
| Předmět: |
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Molecular Stereochemistry Clinical Biochemistry Organophosphonates Pharmaceutical Science Biochemistry Catalysis chemistry.chemical_compound Structure-Activity Relationship Biosynthesis Deoxyadenosine Bacterial Proteins Alanine—tRNA ligase Drug Discovery Humans Peptide Synthases Molecular Biology Antibacterial agent chemistry.chemical_classification DNA ligase Sulfonamides Adenine Nucleotides Organic Chemistry RNA Ligase (ATP) Phosphonate Streptococcus pneumoniae chemistry Serine—tRNA ligase Molecular Medicine Peptidoglycan |
| Zdroj: | Bioorganicmedicinal chemistry. 17(9) |
| ISSN: | 1464-3391 |
| Popis: | Ligase MurM catalyses the addition of Ala from alanyl-tRNA(Ala), or Ser from seryl-tRNA(Ser), to lipid intermediate II in peptidoglycan biosynthesis in Streptococcus pneumoniae, and is a determinant of high-level penicillin resistance. Phosphorus-based transition state analogues were designed as inhibitors of the MurM-catalysed reaction. Phosphonamide analogues mimicking the attack of a lysine nucleophile upon Ala-tRNA(Ala) showed no inhibition of MurM, but adenosine 3'-phosphonate analogues showed inhibition of MurM, the most active being a 2'-deoxyadenosine analogue (IC50 100 mu M). Structure/function studies upon this analogue established that modi. cation of the amino group of the aminoalkylphosphonate resulted in loss of potency, and modi. cation of the adenosine 5'-hydroxyl group with either a t-butyl dimethyl silyl or a carbamate functional group resulted in loss of activity. A library of 48 aryl sulfonamides was also screened against MurM using a radiochemical assay, and two compounds showed sub-millimolar inhibition. These compounds are the first small molecule inhibitors of the Fem ligase family of peptidyltransferases found in Gram-positive bacteria. (C) 2009 Elsevier Ltd. All rights reserved. |
| Databáze: | OpenAIRE |
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