ENTRY ko01502 Pathway NAME Vancomycin resistance DESCRIPTION Vancomycin (VCM) is a glycopeptide antibiotic agent that inhibits the synthesis of peptidolgycan in the production of bacterial cell walls. It is active in most Gram-positive bacteria and acts by binding to the D-Ala-D-Ala C-terminus of pentapeptide, thus blocking the addition of subunits to the peptidoglycan backbone. The resistance to VCM was first described among enterococci in the late 1980s in Europe. Subsequently, vancomycin-resistant enteococci (VRE) have been observed in many countries. The genes encoding resistance are carried on plasmids that can tranfer themselves from cell to cell and on tranponsons that can jump from plamids to the chromosome. Up to now, at least six resistance operon types are characterized, namely VanA, VanB, VanC, VanD, VanE and VanG. The VanA and VanB operons are detected on plasmids or in the chromosome, whereas the rest are found in the chromosome. In addition, Streptomyces, which is non-pathogenic, non-glycopeptide-producing actinomycete, also shows high-level resistance to VCM. In Streptomyces, novel genes (vanK and vanJ) are characterized with no counterparts found in the resistance clusters of pathogenic bacteria. The expression of vancomycin resistance pathway is induced by the VanS-VanR two component system, and D-Ala-D-Lac or D-Ala-D-Ser dipsipeptides are formed in place of D-Ala-D-Ala dipeptide. Thus, VCM cannot bind to pentadepsipeptide[D-Lac] or pentadepsipeptide[D-Ser]. The D-Ala-D-Lac variation shows high levels of resistance to VCM, especially in VanA type, wheras the D-Ala-D-Ser variation shows low levels of resistance. The modified pepidoglycan can interact with cross-linking enzymes (PBPs), thus cell wall is successfully formed. CLASS Human Diseases; Drug resistance: antimicrobial PATHWAY_MAP ko01502 Vancomycin resistance MODULE M00651 Vancomycin resistance, D-Ala-D-Lac type [PATH:ko01502] M00652 Vancomycin resistance, D-Ala-D-Ser type [PATH:ko01502] REFERENCE PMID:16323116 AUTHORS Courvalin P TITLE Vancomycin resistance in gram-positive cocci. JOURNAL Clin Infect Dis 42 Suppl 1:S25-34 (2006) DOI:10.1086/491711 REFERENCE PMID:22913355 AUTHORS Chancey ST, Zahner D, Stephens DS TITLE Acquired inducible antimicrobial resistance in Gram-positive bacteria. JOURNAL Future Microbiol 7:959-78 (2012) DOI:10.2217/fmb.12.63 REFERENCE PMID:8899966 AUTHORS Arthur M, Reynolds P, Courvalin P TITLE Glycopeptide resistance in enterococci. JOURNAL Trends Microbiol 4:401-7 (1996) DOI:10.1016/0966-842X(96)10063-9 REFERENCE PMID:11023964 AUTHORS Cetinkaya Y, Falk P, Mayhall CG TITLE Vancomycin-resistant enterococci. JOURNAL Clin Microbiol Rev 13:686-707 (2000) DOI:10.1128/CMR.13.4.686-707.2000 REFERENCE PMID:7854121 AUTHORS Reynolds PE, Depardieu F, Dutka-Malen S, Arthur M, Courvalin P TITLE Glycopeptide resistance mediated by enterococcal transposon Tn1546 requires production of VanX for hydrolysis of D-alanyl-D-alanine. JOURNAL Mol Microbiol 13:1065-70 (1994) DOI:10.1111/j.1365-2958.1994.tb00497.x REFERENCE PMID:8631706 AUTHORS Evers S, Courvalin P TITLE Regulation of VanB-type vancomycin resistance gene expression by the VanS(B)-VanR (B) two-component regulatory system in Enterococcus faecalis V583. JOURNAL J Bacteriol 178:1302-9 (1996) DOI:10.1128/JB.178.5.1302-1309.1996 REFERENCE PMID:10564477 AUTHORS Reynolds PE, Arias CA, Courvalin P TITLE Gene vanXYC encodes D,D -dipeptidase (VanX) and D,D-carboxypeptidase (VanY) activities in vancomycin-resistant Enterococcus gallinarum BM4174. JOURNAL Mol Microbiol 34:341-9 (1999) DOI:10.1046/j.1365-2958.1999.01604.x REFERENCE PMID:12047383 AUTHORS Podmore AH, Reynolds PE TITLE Purification and characterization of VanXY(C), a D,D-dipeptidase/D,D-carboxypeptidase in vancomycin-resistant Enterococcus gallinarum BM4174. JOURNAL Eur J Biochem 269:2740-6 (2002) DOI:10.1046/j.1432-1033.2002.02946.x REFERENCE PMID:15616270 AUTHORS Reynolds PE, Courvalin P TITLE Vancomycin resistance in enterococci due to synthesis of precursors terminating in D-alanyl-D-serine. JOURNAL Antimicrob Agents Chemother 49:21-5 (2005) DOI:10.1128/AAC.49.1.21-25.2005 REFERENCE PMID:10878136 AUTHORS Arias CA, Weisner J, Blackburn JM, Reynolds PE TITLE Serine and alanine racemase activities of VanT: a protein necessary for vancomycin resistance in Enterococcus gallinarum BM4174. JOURNAL Microbiology 146 ( Pt 7):1727-34 (2000) DOI:10.1099/00221287-146-7-1727 REFERENCE PMID:18792691 AUTHORS Hong HJ, Hutchings MI, Buttner MJ TITLE Vancomycin resistance VanS/VanR two-component systems. JOURNAL Adv Exp Med Biol 631:200-13 (2008) DOI:10.1007/978-0-387-78885-2_14 REFERENCE PMID:14617152 AUTHORS Depardieu F, Bonora MG, Reynolds PE, Courvalin P TITLE The vanG glycopeptide resistance operon from Enterococcus faecalis revisited. JOURNAL Mol Microbiol 50:931-48 (2003) DOI:10.1046/j.1365-2958.2003.03737.x REFERENCE PMID:11036060 AUTHORS McKessar SJ, Berry AM, Bell JM, Turnidge JD, Paton JC TITLE Genetic characterization of vanG, a novel vancomycin resistance locus of Enterococcus faecalis. JOURNAL Antimicrob Agents Chemother 44:3224-8 (2000) DOI:10.1128/AAC.44.11.3224-3228.2000 REFERENCE PMID:23836175 AUTHORS Kwun MJ, Novotna G, Hesketh AR, Hill L, Hong HJ TITLE In vivo studies suggest that induction of VanS-dependent vancomycin resistance requires binding of the drug to D-Ala-D-Ala termini in the peptidoglycan cell wall. JOURNAL Antimicrob Agents Chemother 57:4470-80 (2013) DOI:10.1128/AAC.00523-13 REFERENCE PMID:15130128 AUTHORS Hong HJ, Hutchings MI, Neu JM, Wright GD, Paget MS, Buttner MJ TITLE Characterization of an inducible vancomycin resistance system in Streptomyces coelicolor reveals a novel gene (vanK) required for drug resistance. JOURNAL Mol Microbiol 52:1107-21 (2004) DOI:10.1111/j.1365-2958.2004.04032.x REFERENCE PMID:15632111 AUTHORS Hong HJ, Hutchings MI, Hill LM, Buttner MJ TITLE The role of the novel Fem protein VanK in vancomycin resistance in Streptomyces coelicolor. JOURNAL J Biol Chem 280:13055-61 (2005) DOI:10.1074/jbc.M413801200 REFERENCE PMID:16420361 AUTHORS Hutchings MI, Hong HJ, Buttner MJ TITLE The vancomycin resistance VanRS two-component signal transduction system of Streptomyces coelicolor. JOURNAL Mol Microbiol 59:923-35 (2006) DOI:10.1111/j.1365-2958.2005.04953.x REFERENCE PMID:21569315 AUTHORS Hesketh A, Hill C, Mokhtar J, Novotna G, Tran N, Bibb M, Hong HJ TITLE Genome-wide dynamics of a bacterial response to antibiotics that target the cell envelope. JOURNAL BMC Genomics 12:226 (2011) DOI:10.1186/1471-2164-12-226 REFERENCE PMID:20383152 AUTHORS Koteva K, Hong HJ, Wang XD, Nazi I, Hughes D, Naldrett MJ, Buttner MJ, Wright GD TITLE A vancomycin photoprobe identifies the histidine kinase VanSsc as a vancomycin receptor. JOURNAL Nat Chem Biol 6:327-9 (2010) DOI:10.1038/nchembio.350 REL_PATHWAY ko00550 Peptidoglycan biosynthesis ///