Analysis of peptidoglycan precursors in vancomycin-resistant Enterococcus gallinarum BM4174.
Vancomycin resistance in enterococci is an increasing clinical problem, and several phenotypes have been identified. We demonstrate here that the resistance mechanism in the constitutively vancomycin-resistant Enterococcus gallinarum BM4174 involves an altered pathway of peptidoglycan synthesis and hydrolysis of the normal precursors in the vancomycin-sensitive pathway. A ligase encoded by the vanC gene catalyses synthesis of D-Ala-D-Ser and substitutes this dipeptide for D-Ala-D-Ala in peptidoglycan precursors. It is presumed that this substitution lowers the affinity of vancomycin for its target site. Destruction of D-Ala-D-Ala (D,D-peptidase activity) and of UDP-MurNAc-L-Ala-D-isoGlu-L-Lys-D-Ala-D-Ala by removal of the terminal D-Ala residue (D,D-carboxypeptidase activity) ensures that the normal vancomycin-sensitive pathway of peptidoglycan synthesis cannot function in the resistant strain.
Department of Biochemistry, University of Cambridge, U.K.
P E
PE
Reynolds
H A
HA
Snaith
A J
AJ
Maguire
S
S
Dutka-Malen
P
P
Courvalin
D000595:Amino Acid Sequence; D001665:Binding Sites; D002268:Carboxypeptidases / Q000378:metabolism; D004352:Drug Resistance, Microbial / Q000235:genetics; D010450:Endopeptidases / Q000378:metabolism; D016983:Enterococcus / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism*; D005798:Genes, Bacterial; D008969:Molecular Sequence Data; D010457:Peptidoglycan / Q000235:genetics / Q000378:metabolism*; D010641:Phenotype; D011498:Protein Precursors / Q000235:genetics / Q000378:metabolism*; D014640:Vancomycin / Q000494:pharmacology*
D010457:Peptidoglycan; D011498:Protein Precursors; D014640:Vancomycin; D002268:Carboxypeptidases; D010450:Endopeptidases