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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

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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
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:
DateEvent
1 May 2009Published
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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