PMID- 22085339
OWN - NLM
STAT- MEDLINE
DCOM- 20120308
LR  - 20211203
IS  - 1520-4804 (Electronic)
IS  - 0022-2623 (Linking)
VI  - 54
IP  - 24
DP  - 2011 Dec 22
TI  - Mechanistic analysis of muraymycin analogues: a guide to the design of MraY 
      inhibitors.
PG  - 8421-39
LID - 10.1021/jm200906r [doi]
AB  - The systematic structure-activity relationship (SAR) of the muraymycins (MRYs) 
      using an Ugi four-component reaction (U4CR) was investigated. The impact of the 
      lipophilic substituent on antibacterial activity was significant, and the 
      analogues 8 and 9 having a lipophilic side chain exhibited good activity against 
      a range of Gram-positive bacterial pathogens, including MRSA and VRE. Further 
      investigation of compounds 8 and 9 revealed these analogues to be selective 
      inhibitors of the MraY transferase and nontoxic to HepG2 cells. The SAR of the 
      accessory urea-peptide moiety indicated that it could be simplified. Our SAR 
      study of the MRYs suggests a probable mechanism for inhibition of the MraY, where 
      the inner moiety of the urea-dipeptide motif interacts with the carbohydrate 
      recognition domain in the cytoplasmic loop 5. The predicted binding model would 
      provide further direction toward the design of potent MraY inhibitors. This study 
      has set the stage for the generation of novel antibacterial "lead" compounds 
      based on MRYs.
FAU - Tanino, Tetsuya
AU  - Tanino T
AD  - Faculty of Pharmaceutical Sciences, Hokkaido University, Kita-12, Nishi-6, 
      Kita-ku, Sapporo 060-0812, Japan.
FAU - Al-Dabbagh, Bayan
AU  - Al-Dabbagh B
FAU - Mengin-Lecreulx, Dominique
AU  - Mengin-Lecreulx D
FAU - Bouhss, Ahmed
AU  - Bouhss A
FAU - Oyama, Hiroshi
AU  - Oyama H
FAU - Ichikawa, Satoshi
AU  - Ichikawa S
FAU - Matsuda, Akira
AU  - Matsuda A
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20111115
PL  - United States
TA  - J Med Chem
JT  - Journal of medicinal chemistry
JID - 9716531
RN  - 0 (Anti-Bacterial Agents)
RN  - 0 (Bacterial Proteins)
RN  - 0 (Nucleosides)
RN  - 0 (Peptides)
RN  - 0 (muraymycin D2)
RN  - EC 2.- (Transferases)
RN  - EC 2.7.8.- (Transferases (Other Substituted Phosphate Groups))
RN  - EC 2.7.8.13 (mraY protein, Bacteria)
SB  - IM
MH  - Anti-Bacterial Agents/*chemical synthesis/chemistry/pharmacology
MH  - Bacterial Proteins/*antagonists & inhibitors
MH  - Drug Resistance, Bacterial
MH  - Enterococcus faecalis/drug effects
MH  - Enterococcus faecium/drug effects
MH  - Hep G2 Cells
MH  - Humans
MH  - Microbial Sensitivity Tests
MH  - Models, Molecular
MH  - Molecular Conformation
MH  - Nucleosides/*chemical synthesis/chemistry/pharmacology
MH  - Peptides/*chemical synthesis/chemistry/pharmacology
MH  - Protein Binding
MH  - Staphylococcus aureus/drug effects
MH  - Stereoisomerism
MH  - Structure-Activity Relationship
MH  - Transferases/*antagonists & inhibitors
MH  - Transferases (Other Substituted Phosphate Groups)
EDAT- 2011/11/17 06:00
MHDA- 2012/03/09 06:00
CRDT- 2011/11/17 06:00
PHST- 2011/11/17 06:00 [entrez]
PHST- 2011/11/17 06:00 [pubmed]
PHST- 2012/03/09 06:00 [medline]
AID - 10.1021/jm200906r [doi]
PST - ppublish
SO  - J Med Chem. 2011 Dec 22;54(24):8421-39. doi: 10.1021/jm200906r. Epub 2011 Nov 15.