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.

Human Diseases; Drug resistance: antimicrobial
BRITE hierarchy

Shewanella denitrificans [GN:sdn]

PMID:16323116

Courvalin P

Vancomycin resistance in gram-positive cocci.

Clin Infect Dis 42 Suppl 1:S25-34 (2006)
DOI:10.1086/491711

PMID:22913355

Chancey ST, Zahner D, Stephens DS

Acquired inducible antimicrobial resistance in Gram-positive bacteria.

Future Microbiol 7:959-78 (2012)
DOI:10.2217/fmb.12.63

PMID:8899966

Arthur M, Reynolds P, Courvalin P

Glycopeptide resistance in enterococci.

Trends Microbiol 4:401-7 (1996)
DOI:10.1016/0966-842X(96)10063-9

PMID:11023964

Cetinkaya Y, Falk P, Mayhall CG

Vancomycin-resistant enterococci.

Clin Microbiol Rev 13:686-707 (2000)
DOI:10.1128/CMR.13.4.686-707.2000

PMID:7854121

Reynolds PE, Depardieu F, Dutka-Malen S, Arthur M, Courvalin P

Glycopeptide resistance mediated by enterococcal transposon Tn1546 requires production of VanX for hydrolysis of D-alanyl-D-alanine.

Mol Microbiol 13:1065-70 (1994)
DOI:10.1111/j.1365-2958.1994.tb00497.x

PMID:8631706

Evers S, Courvalin P

Regulation of VanB-type vancomycin resistance gene expression by the VanS(B)-VanR (B) two-component regulatory system in Enterococcus faecalis V583.

J Bacteriol 178:1302-9 (1996)
DOI:10.1128/JB.178.5.1302-1309.1996

PMID:10564477

Reynolds PE, Arias CA, Courvalin P

Gene vanXYC encodes D,D -dipeptidase (VanX) and D,D-carboxypeptidase (VanY) activities in vancomycin-resistant Enterococcus gallinarum BM4174.

Mol Microbiol 34:341-9 (1999)
DOI:10.1046/j.1365-2958.1999.01604.x

PMID:12047383

Podmore AH, Reynolds PE

Purification and characterization of VanXY(C), a D,D-dipeptidase/D,D-carboxypeptidase in vancomycin-resistant Enterococcus gallinarum BM4174.

Eur J Biochem 269:2740-6 (2002)
DOI:10.1046/j.1432-1033.2002.02946.x

PMID:15616270

Reynolds PE, Courvalin P

Vancomycin resistance in enterococci due to synthesis of precursors terminating in D-alanyl-D-serine.

Antimicrob Agents Chemother 49:21-5 (2005)
DOI:10.1128/AAC.49.1.21-25.2005

PMID:10878136

Arias CA, Weisner J, Blackburn JM, Reynolds PE

Serine and alanine racemase activities of VanT: a protein necessary for vancomycin resistance in Enterococcus gallinarum BM4174.

Microbiology 146 ( Pt 7):1727-34 (2000)
DOI:10.1099/00221287-146-7-1727

PMID:18792691

Hong HJ, Hutchings MI, Buttner MJ

Vancomycin resistance VanS/VanR two-component systems.

Adv Exp Med Biol 631:200-13 (2008)
DOI:10.1007/978-0-387-78885-2_14

PMID:14617152

Depardieu F, Bonora MG, Reynolds PE, Courvalin P

The vanG glycopeptide resistance operon from Enterococcus faecalis revisited.

Mol Microbiol 50:931-48 (2003)
DOI:10.1046/j.1365-2958.2003.03737.x

PMID:11036060

McKessar SJ, Berry AM, Bell JM, Turnidge JD, Paton JC

Genetic characterization of vanG, a novel vancomycin resistance locus of Enterococcus faecalis.

Antimicrob Agents Chemother 44:3224-8 (2000)
DOI:10.1128/AAC.44.11.3224-3228.2000

PMID:23836175

Kwun MJ, Novotna G, Hesketh AR, Hill L, Hong HJ

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.

Antimicrob Agents Chemother 57:4470-80 (2013)
DOI:10.1128/AAC.00523-13

PMID:15130128

Hong HJ, Hutchings MI, Neu JM, Wright GD, Paget MS, Buttner MJ

Characterization of an inducible vancomycin resistance system in Streptomyces coelicolor reveals a novel gene (vanK) required for drug resistance.

Mol Microbiol 52:1107-21 (2004)
DOI:10.1111/j.1365-2958.2004.04032.x

PMID:15632111

Hong HJ, Hutchings MI, Hill LM, Buttner MJ

The role of the novel Fem protein VanK in vancomycin resistance in Streptomyces coelicolor.

J Biol Chem 280:13055-61 (2005)
DOI:10.1074/jbc.M413801200

PMID:16420361

Hutchings MI, Hong HJ, Buttner MJ

The vancomycin resistance VanRS two-component signal transduction system of Streptomyces coelicolor.

Mol Microbiol 59:923-35 (2006)
DOI:10.1111/j.1365-2958.2005.04953.x

PMID:21569315

Hesketh A, Hill C, Mokhtar J, Novotna G, Tran N, Bibb M, Hong HJ

Genome-wide dynamics of a bacterial response to antibiotics that target the cell envelope.

BMC Genomics 12:226 (2011)
DOI:10.1186/1471-2164-12-226

PMID:20383152

Koteva K, Hong HJ, Wang XD, Nazi I, Hughes D, Naldrett MJ, Buttner MJ, Wright GD

A vancomycin photoprobe identifies the histidine kinase VanSsc as a vancomycin receptor.

Nat Chem Biol 6:327-9 (2010)
DOI:10.1038/nchembio.350