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Inhibition of tRNA-dependent ligase MurM from Streptococcus pneumoniae by phosphonate and sulfonamide inhibitors
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Cressina, Elena, Lloyd, Adrian J., De Pascale, Gianfranco, Mok, B. James, Caddick, Stephen, Roper, David I., Dowson, Christopher G. and Bugg, Tim (2009) Inhibition of tRNA-dependent ligase MurM from Streptococcus pneumoniae by phosphonate and sulfonamide inhibitors. Bioorganic & Medicinal Chemistry, Vol.17 (No.9). pp. 3443-3455. doi:10.1016/j.bmc.2009.03.028 ISSN 0968-0896.
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Official URL: http://dx.doi.org/10.1016/j.bmc.2009.03.028
Abstract
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.
| Item Type: | Journal Article | ||||
|---|---|---|---|---|---|
| Subjects: | Q Science > QD Chemistry Q Science > QP Physiology Q Science > QR Microbiology |
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| Divisions: | Faculty of Science, Engineering and Medicine > Science > Chemistry | ||||
| Library of Congress Subject Headings (LCSH): | Peptidoglycans -- Synthesis, Streptococcus pneumoniae, Ligases, Chemical inhibitors, Antibacterial agents | ||||
| Journal or Publication Title: | Bioorganic & Medicinal Chemistry | ||||
| Publisher: | Elsevier | ||||
| ISSN: | 0968-0896 | ||||
| Official Date: | 1 May 2009 | ||||
| Dates: |
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| Volume: | Vol.17 | ||||
| Number: | No.9 | ||||
| Number of Pages: | 13 | ||||
| Page Range: | pp. 3443-3455 | ||||
| DOI: | 10.1016/j.bmc.2009.03.028 | ||||
| Status: | Peer Reviewed | ||||
| Publication Status: | Published | ||||
| Access rights to Published version: | Restricted or Subscription Access | ||||
| Funder: | Sixth Framework Programme (European Commission) (FP6), Medical Research Council (Great Britain) (MRC), Wellcome Trust (London, England), Biotechnology and Biological Sciences Research Council (Great Britain) (BBSRC), University of Warwick | ||||
| Grant number: | G0400848 (MRC), 066443 (WT) |
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