Inhibition of tRNA-dependent ligase MurM from Streptococcus pneumoniae by phosphonate and sulfonamide inhibitors.
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.
Department of Chemistry, University of Warwick, Coventry, UK.
Elena
E
Cressina
Adrian J
AJ
Lloyd
Gianfranco
G
De Pascale
B
B
James Mok
Stephen
S
Caddick
David I
DI
Roper
Christopher G
CG
Dowson
Timothy D H
TD
Bugg
D000227:Adenine Nucleotides / Q000737:chemistry; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors*; D002384:Catalysis; D006801:Humans; D008958:Models, Molecular; D063065:Organophosphonates / Q000737:chemistry / Q000494:pharmacology*; D010453:Peptide Synthases / Q000037:antagonists & inhibitors*; D011130:RNA Ligase (ATP) / Q000235:genetics; D013296:Streptococcus pneumoniae / Q000187:drug effects / Q000201:enzymology*; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000737:chemistry / Q000494:pharmacology*
D000227:Adenine Nucleotides; D001426:Bacterial Proteins; D063065:Organophosphonates; D013449:Sulfonamides; C408066:MurM protein, Streptococcus pneumoniae; D010453:Peptide Synthases; D011130:RNA Ligase (ATP)