Inhibition of tRNA-dependent ligase MurM from Streptococcus pneumoniae by phosphonate and sulfonamide inhibitors |
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Authors: | Elena Cressina Adrian J. Lloyd Gianfranco De Pascale B. James Mok Stephen Caddick David I. Roper Christopher G. Dowson Timothy D.H. Bugg |
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Affiliation: | 1. Department of Chemistry, University of Warwick, Coventry CV4 7AL, UK;2. Department of Biological Sciences, University of Warwick, Coventry CV4 7AL, UK;3. Department of Chemistry, University College London, 20 Gower Street, London WC1H 0AJ, UK |
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Abstract: | Ligase MurM catalyses the addition of Ala from alanyl-tRNAAla, or Ser from seryl-tRNASer, 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-tRNAAla showed no inhibition of MurM, but adenosine 3′-phosphonate analogues showed inhibition of MurM, the most active being a 2′-deoxyadenosine analogue (IC50 100 μM). Structure/function studies upon this analogue established that modification of the amino group of the aminoalkylphosphonate resulted in loss of potency, and modification 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. |
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