PMID- 19356937
OWN - NLM
STAT- MEDLINE
DCOM- 20091209
LR  - 20211020
IS  - 1464-3391 (Electronic)
IS  - 0968-0896 (Linking)
VI  - 17
IP  - 9
DP  - 2009 May 1
TI  - Inhibition of tRNA-dependent ligase MurM from Streptococcus pneumoniae by 
      phosphonate and sulfonamide inhibitors.
PG  - 3443-55
LID - 10.1016/j.bmc.2009.03.028 [doi]
AB  - 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 (IC(50) 100 microM). 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.
FAU - Cressina, Elena
AU  - Cressina E
AD  - Department of Chemistry, University of Warwick, Coventry, UK.
FAU - Lloyd, Adrian J
AU  - Lloyd AJ
FAU - De Pascale, Gianfranco
AU  - De Pascale G
FAU - James Mok, B
AU  - James Mok B
FAU - Caddick, Stephen
AU  - Caddick S
FAU - Roper, David I
AU  - Roper DI
FAU - Dowson, Christopher G
AU  - Dowson CG
FAU - Bugg, Timothy D H
AU  - Bugg TD
LA  - eng
GR  - G0400848/MRC_/Medical Research Council/United Kingdom
GR  - G0500643/MRC_/Medical Research Council/United Kingdom
GR  - G0701400/MRC_/Medical Research Council/United Kingdom
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20090321
PL  - England
TA  - Bioorg Med Chem
JT  - Bioorganic & medicinal chemistry
JID - 9413298
RN  - 0 (Adenine Nucleotides)
RN  - 0 (Bacterial Proteins)
RN  - 0 (Organophosphonates)
RN  - 0 (Sulfonamides)
RN  - EC 6.3.2.- (MurM protein, Streptococcus pneumoniae)
RN  - EC 6.3.2.- (Peptide Synthases)
RN  - EC 6.5.1.3 (RNA Ligase (ATP))
SB  - IM
MH  - Adenine Nucleotides/chemistry
MH  - Bacterial Proteins/*antagonists & inhibitors
MH  - Catalysis
MH  - Humans
MH  - Models, Molecular
MH  - Organophosphonates/chemistry/*pharmacology
MH  - Peptide Synthases/*antagonists & inhibitors
MH  - RNA Ligase (ATP)/genetics
MH  - Streptococcus pneumoniae/drug effects/*enzymology
MH  - Structure-Activity Relationship
MH  - Sulfonamides/chemistry/*pharmacology
EDAT- 2009/04/10 09:00
MHDA- 2009/12/16 06:00
CRDT- 2009/04/10 09:00
PHST- 2008/12/04 00:00 [received]
PHST- 2009/03/14 00:00 [accepted]
PHST- 2009/04/10 09:00 [entrez]
PHST- 2009/04/10 09:00 [pubmed]
PHST- 2009/12/16 06:00 [medline]
AID - S0968-0896(09)00265-X [pii]
AID - 10.1016/j.bmc.2009.03.028 [doi]
PST - ppublish
SO  - Bioorg Med Chem. 2009 May 1;17(9):3443-55. doi: 10.1016/j.bmc.2009.03.028. Epub 
      2009 Mar 21.