Abstract
Glycopeptides are one of the oldest but still critically important antibiotic class that target Gram-positive pathogens. They are used as essential drugs for the treatment of life-threatening infections of relevant pathogens such as Staphylococcus aureus, Enterococcus spp., and Clostridium difficile. Antibacterial glycopeptides arrest bacterial cell wall biosynthesis by binding to the acyl-d-alanyl-d-alanine terminus of the nascent peptidoglycan, blocking its extracellular polymerization, and subsequently inhibiting cell growth and division. Chemically, these agents consist of a heptapeptide core structure that is transformed in the mature active antibiotic by intramolecular cyclizations among aromatic amino acid residues and by addition of glycosidic moieties, chlorine atoms, and occasionally lipid chains. First-generation glycopeptides (vancomycin and teicoplanin) are natural products from soil actinomycetes. Second-generation molecules (dalbavancin, oritavancin, telavancin) are produced by chemical modification of natural products. Glycopeptide resistance required nearly 30 years to appear following clinical introduction of vancomycin. High-level resistance is due to a collection of genes (named van) that reorder cell wall biosynthesis enabling bacteria to bypass the critical steps susceptible to inhibition by vancomycin and other glycopeptide antibiotics. There have been various efforts, with mixed success, to identify novel glycopeptide structures able to circumvent high-level glycopeptide resistance. This chapter is an overview on the features, mode of action, mechanism of resistance, biosynthesis of this old but up-to-date successful antibiotic class.
Keywords
- Skin Structure Infection
- Glycopeptide Antibiotic
- Biosynthetic Cluster
- Glycopeptide Resistance
- Peptidoglycan Precursor
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.
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Arnusch CJ, Bonvin AM, Verel AM, Jansen WT, Liskamp RM, de Kruijff B, Pieters RJ, Breukink E (2008) The vancomycin-nisin (1–12) hybrid restores activity against vancomycin resistant enterococci. Biochemistry 47:12661–12663
Arthur M, Reynolds PE, Depardieu F, Evers S, Dutka-Malen S, Quintiliani R, Courvalin P (1996) Mechanisms of glycopeptide resistance in enterococci. J Infect 32:11–16
Ashford PA, Bew SP (2012) Recent advances in the synthesis of new glycopeptide antibiotics. Chem Soc Rev 41:957–978
Bager F, Aarestrup FM, Madsen M, Wegener HC (1999) Glycopeptide resistance in Enterococcus faecium from broilers and pigs following discontinued use of avoparcin. Microb Drug Resist 5:53–56
Banik JJ, Brady SF (2008) Cloning and characterization of new glycopeptide gene clusters found in an environmental DNA megalibrary. Proc Natl Acad Sci USA 105:17273–17277
Banik JJ, Craig JW, Calle PY, Brady SF (2010) Tailoring enzyme-rich environmental DNA clones: a source of enzymes for generating libraries of unnatural natural products. J Am Chem Soc 132:15661–15670
Belley A, McKay GA, Arhin FF, Sarmiento I, Beaulieu S, Fadhil I, Parr TR, Moeck G (2010) Oritavancin disrupts membrane integrity of Staphylococcus aureus and vancomycin-resistant enterococci to effect rapid bacterial killing. Antimicrob Agents Chemother 54:5369–5371
Beltrametti F, Consolandi A, Carrano L, Bagatin F, Rossi R, Leoni L, Zennaro E, Selva E, Marinelli F (2007) Resistance to glycopeptide antibiotics in the teicoplanin producer is mediated by van gene homologue expression directing the synthesis of a modified cell wall peptidoglycan. Antimicrob Agents Chemother 51:1135–1141
Binda E, Marcone GL, Pollegioni L, Marinelli F (2012) Characterization of VanYn, a novel d,d-peptidase/d,d-carboxypeptidase involved in glycopeptide antibiotic resistance in Nonomuraea sp. ATCC 39727. FEBS J 279:3203–3213
Binda E, Marcone GL, Berini F, Pollegioni L, Marinelli F (2013) Streptomyces spp. as efficient expression system for a d, d-peptidase/d,d-carboxypeptidase involved in glycopeptide antibiotic resistance. BMC Biotechnol 13:24
Boeck LD, Mertz FP (1986) A47934, a novel glycopeptide-aglycone antibiotic produced by a strain of Streptomyces toyocaensis taxonomy and fermentation studies. J Antibiot (Tokyo) 39:1533–1540
Borghi A, Edwards D, Zerilli LF, Lancini GC (1991) Factors affecting the normal and branched-chain acyl moieties of teicoplanin components produced by Actinoplanes teichomyceticus. J Gen Microbiol 137:587–592
Bouza E, Burillo A (2010) Oritavancin: a novel lipoglycopeptide active against gram-positive pathogens including multiresistant strains. Int J Antimicrob Agents 36:401–407
Bugg TD, Wright GD, Dutka-Malen S, Arthur M, Courvalin P, Walsh CT (1991) Molecular basis for vancomycin resistance in Enterococcus faecium BM4147: biosynthesis of a depsipeptide peptidoglycan precursor by vancomycin resistance proteins VanH and VanA. Biochemistry 30:10408–10415
Chan HC, Huang YT, Lyu SY, Huang CJ, Li YS, Liu YC, Chou CC, Tsai MD, Li TL (2011) Regioselective deacetylation based on teicoplanin-complexed orf2* crystal structures. Mol BioSyst 7:1224–1231
Choroba OW, Williams DH, Spencer JB (2000) Biosynthesis of the vancomycin group of antibiotics: involvement of an unusual dioxygenase in the pathway to (s)-4-hydroxyphenylglycine. J Am Chem Soc 122:5389–5390
Crowley BM, Boger DL (2006) Total synthesis and evaluation of [psi[ch2nh]tpg4]vancomycin aglycon: reengineering vancomycin for dual d-Ala-d-Ala and d-Ala-d-Lac binding. J Am Chem Soc 128:2885–2892
D’Costa VM, King CE, Kalan L, Morar M, Sung WW, Schwarz C, Froese D, Zazula G, Calmels F, Debruyne R, Golding GB, Poinar HN, Wright GD (2011) Antibiotic resistance is ancient. Nature 477:457–461
Ehrenkranz NJ (1958) The clinical evaluation of vancomycin in treatment of multi-antibiotic refractory staphylococcal infections. Antibiot Annu 6:587–594
Evers S, Quintiliani R, Courvalin P (1996) Genetics of glycopeptide resistance in enterococci. Microb Drug Resist 2:219–223
Fu X, Albermann C, Jiang J, Liao J, Zhang C, Thorson JS (2003) Antibiotic optimization via in vitro glycorandomization. Nat Biotechnol 21:1467–1469
Geraci JE, Hermans PE (1983) Vancomycin. Mayo Clin Proc 58:88–91
Goldstein BP, Selva E, Gastaldo L, Berti M, Pallanza R, Ripamonti F, Ferrari P, Denaro M, Arioli V, Cassani G (1987) A40926, a new glycopeptide antibiotic with anti-Neisseria activity. Antimicrob Agents Chemother 31:1961–1966
Gravet A, Rondeau M, Harf-Monteil C, Grunenberger F, Monteil H, Scheftel JM, Prévost G (1999) Predominant Staphylococcus aureus isolated from antibiotic-associated diarrhea is clinically relevant and produces enterotoxin A and the bicomponent toxin lukE-lukD. J Clin Microbiol 37:4012–4019
Grdadolnik SG, Pristovsek P, Mierke DF (1998) Vancomycin: conformational consequences of the sugar substituent. J Med Chem 41:2090–2099
Guskey MT, Tsuji BT (2010) A comparative review of the lipoglycopeptides: oritavancin, dalbavancin, and telavancin. Pharmacotherapy 30:80–94
Hammond SJ, Williamson MP, Williams DH, Boeck LD, Marconi GG (1982) On the biosynthesis of the antibiotic vancomycin. J Chem Soc Chem Commun 344–346
Healy VL, Lessard IA, Roper DI, Knox JR, Walsh CT (2000) Vancomycin resistance in enterococci: reprogramming of the d-Ala-d-Ala ligases in bacterial peptidoglycan biosynthesis. Chem Biol 7:R109–R119
Higgins DL, Chang R, Debabov DV, Leung J, Wu T, Krause KM, Sandvik E, Hubbard JM, Kaniga K, Schmidt DE, Gao Q, Cass RT, Karr DE, Benton BM, Humphrey PP (2005) Telavancin, a multifunctional lipoglycopeptide, disrupts both cell wall synthesis and cell membrane integrity in methicillin-resistant Staphylococcus aureus. Antimicrob Agents Chemother 49:1127–1134
Hong HJ, Hutchings MI, Neu JM, Wright GD, Paget MS, Buttner MJ (2004) Characterization of an inducible vancomycin resistance system in Streptomyces coelicolor reveals a novel gene (vanK) required for drug resistance. Mol Microbiol 52:1107–1121
Hong HJ, Hutchings MI, Hill LM, Buttner MJ (2005) The role of the novel fem protein VanK in vancomycin resistance in Streptomyces coelicolor. J Biol Chem 280:13055–13061
Hong HJ, Hutchings MI, Buttner MJ (2008) Vancomycin resistance vanS/vanR two-component systems. Adv Exp Med Biol 631:200–213
Howden BP, Davies JK, Johnson PD, Stinear TP, Grayson ML (2010) Reduced vancomycin susceptibility in Staphylococcus aureus, including vancomycin-intermediate and heterogeneous vancomycin-intermediate strains: resistance mechanisms, laboratory detection, and clinical implications. Clin Microbiol Rev 23:99–139
Hutchings MI, Hong HJ, Buttner MJ (2006) The vancomycin resistance VanRS two-component signal transduction system of Streptomyces coelicolor. Mol Microbiol 59:923–935
James RC, Pierce JG, Okano A, Xie J, Boger DL (2012) Redesign of glycopeptide antibiotics: back to the future. ACS Chem Biol 7:797–804
Jovetic S, Zhu Y, Marcone GL, Marinelli F, Tramper J (2010) β-lactam and glycopeptide antibiotics: first and last line of defense? Trends Biotechnol 28:596–604
Kahne D, Leimkuhler C, Lu W, Walsh C (2005) Glycopeptide and lipoglycopeptide antibiotics. Chem Rev 105:425–448
Kalan L, Perry J, Koteva K, Thaker M, Wright G (2013) Glycopeptide sulfation evades resistance. J Bacteriol 195:167–171
Kruse H, Johansen BK, Rørvik LM, Schaller G (1999) The use of avoparcin as a growth promoter and the occurrence of vancomycin-resistant enterococcus species in norwegian poultry and swine production. Microb Drug Resist 5:135–139
Labeda DP (1995) Amycolatopsis coloradensis sp. nov., the avoparcin (ll-av290)-producing strain. Int J Syst Bact 45:124–127
Lamb SS, Patel T, Koteva KP, Wright GD (2006) Biosynthesis of sulfated glycopeptide antibiotics by using the sulfotransferase stal. Chem Biol 13:171–181
Lancini G, Demain A (2006) Bacterial pharmaceutical products. In: Dworkin M, Falkow S, Rosenberg E, Schleifer KH, Stackebrandt E (eds) The Prokaryotes. Vol 1: Symbiotic assosiations, biotechnology, applied microbiology. Springer, Heidelberg
Leadbetter MR, Adams SM, Bazzini B, Fatheree PR, Karr DE, Krause KM, Lam BM, Linsell MS, Nodwell MB, Pace JL, Quast K, Shaw JP, Soriano E, Trapp SG, Villena JD, Wu TX, Christensen BG, Judice JK (2004) Hydrophobic vancomycin derivatives with improved ADME properties: discovery of telavancin (td-6424). J Antibiot (Tokyo) 57:326–336
Lebreton F, Depardieu F, Bourdon N, Fines-Guyon M, Berger P, Camiade S, Leclercq R, Courvalin P, Cattoir V (2011) d-Ala-d-Ser VanN-type transferable vancomycin resistance in Enterococcus faecium. Antimicrob Agents Chemother 55:4606–4612
Lessard IA, Walsh CT (1999) Mutational analysis of active-site residues of the enterococcal d-Ala-d-Ala dipeptidase VanX and comparison with Escherichia coli d-Ala-d-Ala ligase and d-Ala-d-Ala carboxypeptidase VanY. Chem Biol 6:177–187
Levine DP (2006) Vancomycin: a history. Clin Infect Dis 42(Suppl 1):S5–S12
Li TL, Huang F, Haydock SF, Mironenko T, Leadlay PF, Spencer JB (2004) Biosynthetic gene cluster of the glycopeptide antibiotic teicoplanin: characterization of two glycosyltransferases and the key acyltransferase. Chem Biol 11:107–119
Li TL, Liu YC, Lyu SY (2012) Combining biocatalysis and chemoselective chemistries for glycopeptide antibiotics modification. Curr Opin Chem Biol 16:170–178
Liu YC, Li YS, Lyu SY, Hsu LJ, Chen YH, Huang YT, Chan HC, Huang CJ, Chen GH, Chou CC, Tsai MD, Li TL (2011) Interception of teicoplanin oxidation intermediates yields new antimicrobial scaffolds. Nat Chem Biol 7:304–309
Lu K, Asano R, Davies J (2004) Antimicrobial resistance gene delivery in animal feeds. Emerg Infect Dis 10:679–683
Mackay JP, Gerhard U, Beauregard DA, Maplestone RA, Williams DH (1994a) Dissection of the contributions toward dimerization of glycopeptide antibiotics. J Am Chem Soc 116:4573–4580
Mackay JP, Gerhard U, Beauregard DA, Westwell MS, Searle MS, Williams DH (1994b) Glycopeptide antibiotic activity and the possible role of dimerization: a model for biological signaling. J Am Chem Soc 116:4581–4590
Malabarba A, Nicas TI, Thompson RC (1997) Structural modifications of glycopeptide antibiotics. Med Res Rev 17:69–137
Malabarba A, Ciabatti R (2001) Glycopeptide derivatives. Curr Med Chem 8:1759–1773
Malabarba A, Goldstein BP (2005) Origin, structure, and activity in vitro and in vivo of dalbavancin. J Antimicrob Chemother 55(Suppl 2):15–20
Marcone GL, Beltrametti F, Binda E, Carrano L, Foulston L, Hesketh A, Bibb M, Marinelli F (2010) Novel mechanism of glycopeptide resistance in the A40926 producer Nonomuraea sp. ATCC 39727. Antimicrob Agents Chemother 54:2465–2472
Marshall CG, Lessard IA, Park I, Wright GD (1998) Glycopeptide antibiotic resistance genes in glycopeptide-producing organisms. Antimicrob Agents Chemother 42:2215–2220
Matsuzaki K, Ikeda H, Ogino T, Matsumoto A, Woodruff HB, Tanaka H, Omura S (1994) Chloropeptins I and II, novel inhibitors against gp120-CD4 binding from Streptomyces sp. J Antibiot (Tokyo) 47:1173–1174
McCormick MH, McGuire JM, Pittenger GE, Pittenger RC, Stark WM (1955) Vancomycin, a new antibiotic. I. Chemical and biological properties. Antibiot Annu 3:606–611
Neu HC, Prince A, Neu CO, Garvey GJ (1977) Incidence of diarrhea and colitis associated with clindamycin therapy. J Infect Dis 135(Suppl):S120–S125
Nicolaou KC, Boddy CN, Bräse S, Winssinger N (1999) Chemistry, biology, and medicine of the glycopeptide antibiotics. Angew Chem Int Ed Engl 38:2096–2152
Nitanai Y, Kikuchi T, Kakoi K, Hanamaki S, Fujisawa I, Aoki K (2009) Crystal structures of the complexes between vancomycin and cell-wall precursor analogs. J Mol Biol 385:1422–1432
Novotna G, Hill C, Vincent K, Liu C, Hong HJ (2012) A novel membrane protein, VanJ, conferring resistance to teicoplanin. Antimicrob Agents Chemother 56:1784–1796
Pace JL, Yang G (2006) Glycopeptides: update on an old successful antibiotic class. Biochem Pharmacol 71:968–980
Pantosti A, Del Grosso M, Tagliabue S, Macrì A, Caprioli A (1999) Decrease of vancomycin-resistant enterococci in poultry meat after avoparcin ban. Lancet 354:741–742
Parenti F, Beretta G, Berti M, Arioli V (1978) Teichomycins, new antibiotics from Actinoplanes teichomyceticus nov. Sp. I. Description of the producer strain, fermentation studies and biological properties. J Antibiot 31:276–283
Parenti F, Schito GC, Courvalin P (2000) Teicoplanin chemistry and microbiology. J Chemother 12:5–14
Peacock JE, Marsik FJ, Wenzel RP (1980) Methicillin-resistant Staphylococcus aureus: introduction and spread within a hospital. Ann Intern Med 93:526–532
Peetermans WE, Hoogeterp JJ, Hazekamp-van Dokkum AM, van den Broek P, Mattie H (1990) Antistaphylococcal activities of teicoplanin and vancomycin in vitro and in an experimental infection. Antimicrob Agents Chemother 34:1869–1874
Pelzer S, Süssmuth R, Heckmann D, Recktenwald J, Huber P, Jung G, Wohlleben W (1999) Identification and analysis of the balhimycin biosynthetic gene cluster and its use for manipulating glycopeptide biosynthesis in Amycolatopsis mediterranei DSM 5908. Antimicrob Agents Chemother 43:1565–1573
Pensack JM, Wang GT, Simkins L (1982) Avoparcin—a growth-promoting feed antibiotic for broiler chickens. Poult Sci 61:1009–1012
Périchon B, Courvalin P (2009) VanA-type vancomycin-resistant Staphylococcus aureus. Antimicrob Agents Chemother 53:4580–4587
Pootoolal J, Thomas MG, Marshall CG, Neu JM, Hubbard BK, Walsh CT, Wright GD (2002) Assembling the glycopeptide antibiotic scaffold: the biosynthesis of A47934 from Streptomyces toyocaensis NRRL 15009. Proc Natl Acad Sci USA 99:8962–8967
Prince AS, Neu HC (1979) Antibiotic-associated pseudomembranous colitis in children. Pediatr Clin North Am 26:261–268
Puk O, Huber P, Bischoff D, Recktenwald J, Jung G, Süssmuth RD, van Pée KH, Wohlleben W, Pelzer S (2002) Glycopeptide biosynthesis in Amycolatopsis mediterranei DSM 5908: function of a halogenase and a haloperoxidase/perhydrolase. Chem Biol 9:225–235
Puk O, Bischoff D, Kittel C, Pelzer S, Weist S, Stegmann E, Süssmuth RD, Wohlleben W (2004) Biosynthesis of chloro-beta-hydroxytyrosine, a nonproteinogenic amino acid of the peptidic backbone of glycopeptide antibiotics. J Bacteriol 186:6093–6100
Retzlaff L, Distler J (1995) The regulator of streptomycin gene expression, StrR of Streptomyces griseus is a DNA binding activator protein with multiple recognition sites. Mol Microbiol 18:151–162
Reynolds PE, Courvalin P (2005) Vancomycin resistance in enterococci due to synthesis of precursors terminating in d-alanyl-d-serine. Antimicrob Agents Chemother 49:21–25
Rybak MJ, Bailey EM, Warbasse LH (1992) Absence of “Red man syndrome” in patients being treated with vancomycin or high-dose teicoplanin. Antimicrob Agents Chemother 36:1204–1207
Saravolatz LD, Markowitz N, Arking L, Pohlod D, Fisher E (1982a) Methicillin-resistant Staphylococcus aureus. Epidemiologic observations during a community-acquired outbreak. Ann Intern Med 96:11–16
Saravolatz LD, Pohlod DJ, Arking LM (1982b) Community-acquired methicillin-resistant Staphylococcus aureus infections: a new source for nosocomial outbreaks. Ann Intern Med 97:325–329
Schäberle TF, Vollmer W, Frasch HJ, Hüttel S, Kulik A, Röttgen M, von Thaler AK, Wohlleben W, Stegmann E (2011) Self-resistance and cell wall composition in the glycopeptide producer Amycolatopsis balhimycina. Antimicrob Agents Chemother 55:4283–4289
Schäfer M, Schneider TR, Sheldrick GM (1996) Crystal structure of vancomycin. Structure 4:1509–1515
Sosio M, Stinchi S, Beltrametti F, Lazzarini A, Donadio S (2003) The gene cluster for the biosynthesis of the glycopeptide antibiotic A40926 by Nonomuraea species. Chem Biol 10:541–549
Sosio M, Kloosterman H, Bianchi A, de Vreugd P, Dijkhuizen L, Donadio S (2004) Organization of the teicoplanin gene cluster in Actinoplanes teichomyceticus. Microbiology 150:95–102
Stegmann E, Frasch HJ, Wohlleben W (2010) Glycopeptide biosynthesis in the context of basic cellular functions. Curr Opin Microbiol 13:595–602
Sujatha S, Praharaj I (2012) Glycopeptide resistance in Gram-positive cocci: a review. Interdiscip Perspect Infect Dis 2012:781679
Süssmuth RD, Wohlleben W (2004) The biosynthesis of glycopeptide antibiotics -a model for complex, non-ribosomally synthesized, peptidic secondary metabolites. Appl Microbiol Biotechnol 63:344–350
Taurino C, Frattini L, Marcone GL, Gastaldo L, Marinelli F (2011) Actinoplanes teichomyceticus ATCC 31121 as a cell factory for producing teicoplanin. Microb Cell Fact 10:82
Thaker MN, Wright GD (2012) Opportunities for synthetic biology in antibiotics: expanding glycopeptide chemical diversity. ACS Synth Biol doi:10.1021/sb300092n
Uttley AH, George RC, Naidoo J, Woodford N, Johnson AP, Collins CH, Morrison D, Gilfillan AJ, Fitch LE, Heptonstall J (1989) High-level vancomycin-resistant enterococci causing hospital infections. Epidemiol Infect 103:173–181
Van Bambeke F (2006) Glycopeptides and glycodepsipeptides in clinical development: a comparative review of their antibacterial spectrum, pharmacokinetics and clinical efficacy. Curr Opin Investig Drugs 7:740–749
Van Hal SJ, Paterson DL (2011) New Gram-positive antibiotics: better than vancomycin? Curr Opin Infect Dis 24:515–520
Van Wageningen AM, Kirkpatrick PN, Williams DH, Harris BR, Kershaw JK, Lennard NJ, Jones M, Jones SJ, Solenberg PJ (1998) Sequencing and analysis of genes involved in the biosynthesis of a vancomycin group antibiotic. Chem Biol 5:155–162
Vollmer W, Blanot D, de Pedro MA (2008) Peptidoglycan structure and architecture. FEMS Microbiol Rev 32:149–167
Weigel LM, Clewell DB, Gill SR, Clark NC, McDougal LK, Flannagan SE, Kolonay JF, Shetty J, Killgore GE, Tenover FC (2003) Genetic analysis of a high-level vancomycin-resistant isolate of Staphylococcus aureus. Science 302:1569–1571
Williams DH, Searle MS, Mackay JP, Gerhard U, Maplestone RA (1993) Toward an estimation of binding constants in aqueous solution: studies of associations of vancomycin group antibiotics. Proc Natl Acad Sci USA 90:1172–1178
Wohlleben W, Stegmann E, Süssmuth RD (2009) Chapter 18. Molecular genetic approaches to analyze glycopeptide biosynthesis. Methods Enzymol 458:459–486
Xu X, Lin D, Yan G, Ye X, Wu S, Guo Y, Zhu D, Hu F, Zhang Y, Wang F, Jacoby GA, Wang M (2010) vanM, a new glycopeptide resistance gene cluster found in Enterococcus faecium. Antimicrob Agents Chemother 54:4643–4647
Zhanel GG, Calic D, Schweizer F, Zelenitsky S, Adam H, Lagacé-Wiens PR, Rubinstein E, Gin AS, Hoban DJ, Karlowsky JA (2010) New lipoglycopeptides: a comparative review of dalbavancin, oritavancin and telavancin. Drugs 70:859–886
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Marcone, G.L., Marinelli, F. (2014). Glycopeptides: An Old but Up-to-Date Successful Antibiotic Class. In: Marinelli, F., Genilloud, O. (eds) Antimicrobials. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-39968-8_5
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