Editing Vancomycin (section)

===Acquired resistance===
Evolution of [[Antimicrobial resistance|microbial resistance]] to vancomycin is a growing problem, especially in healthcare facilities such as hospitals. While newer alternatives to vancomycin exist, such as [[linezolid]] (2000) and [[daptomycin]] (2003), the widespread use of vancomycin makes resistance to it a significant worry, especially for individual patients if resistant infections are not quickly identified and the patient continues an ineffective treatment. [[Vancomycin-resistant Enterococcus|Vancomycin-resistant ''Enterococcus'']] <!-- (VRE) --> emerged in 1986.<ref name="pmid10706902">{{cite journal |vauthors=Murray BE |title=Vancomycin-resistant enterococcal infections |journal=The New England Journal of Medicine |volume=342 |issue=10 |pages=710–21 |date=March 2000 |pmid=10706902 |doi=10.1056/NEJM200003093421007 |url=https://www.nejm.org/doi/10.1056/NEJM200003093421007 |quote="The first reports of vancomycin-resistant enterococci (later classified as VanA type of resistance) involved strains of E. faecium that were resistant to vancomycin and teicoplanin (another glycopeptide) and that were isolated from patients in France and England in 1986. Vancomycin-resistant E. faecalis, subsequently classified as VanB type, was recovered from patients in Missouri in 1987." |url-access=subscription |access-date=11 September 2022 |archive-date=11 September 2022 |archive-url=https://web.archive.org/web/20220911090912/https://www.nejm.org/doi/10.1056/NEJM200003093421007 |url-status=live }}</ref> Vancomycin resistance evolved in more common pathogenic organisms during the 1990s and 2000s, including [[vancomycin-resistant Staphylococcus aureus|vancomycin-intermediate ''S. aureus'']] (VISA) and [[vancomycin-resistant Staphylococcus aureus|vancomycin-resistant ''S. aureus'']] (VRSA).<ref name="Smith1999">{{cite journal | vauthors = Smith TL, Pearson ML, Wilcox KR, Cruz C, Lancaster MV, Robinson-Dunn B, Tenover FC, Zervos MJ, Band JD, White E, Jarvis WR | title = Emergence of vancomycin resistance in Staphylococcus aureus. Glycopeptide-Intermediate Staphylococcus aureus Working Group | journal = The New England Journal of Medicine | volume = 340 | issue = 7 | pages = 493–501 | date = February 1999 | pmid = 10021469 | doi = 10.1056/NEJM199902183400701 | doi-access = free }}</ref><ref name="McDonald2005">{{cite journal | vauthors = McDonald LC, Killgore GE, Thompson A, Owens RC, Kazakova SV, Sambol SP, Johnson S, Gerding DN | s2cid = 43628397 | title = An epidemic, toxin gene-variant strain of Clostridium difficile | journal = The New England Journal of Medicine | volume = 353 | issue = 23 | pages = 2433–41 | date = December 2005 | pmid = 16322603 | doi = 10.1056/NEJMoa051590 | doi-access = free }}</ref> Agricultural use of [[avoparcin]], another similar glycopeptide antibiotic, may have contributed to the evolution of vancomycin-resistant organisms.<ref name="pmid11168181">{{cite journal | vauthors = Acar J, Casewell M, Freeman J, Friis C, Goossens H | title = Avoparcin and virginiamycin as animal growth promoters: a plea for science in decision-making | journal = Clinical Microbiology and Infection | volume = 6 | issue = 9 | pages = 477–82 | date = September 2000 | pmid = 11168181 | doi = 10.1046/j.1469-0691.2000.00128.x | doi-access = free }}</ref><ref name="pmid9234429">{{cite journal | vauthors = Bager F, Madsen M, Christensen J, Aarestrup FM | title = Avoparcin used as a growth promoter is associated with the occurrence of vancomycin-resistant Enterococcus faecium on Danish poultry and pig farms | journal = Preventive Veterinary Medicine | volume = 31 | issue = 1–2 | pages = 95–112 | date = July 1997 | pmid = 9234429 | doi = 10.1016/S0167-5877(96)01119-1 | s2cid = 4958557 }}</ref><ref name="pmid10474607">{{cite journal | vauthors = Collignon PJ | title = Vancomycin-resistant enterococci and use of avoparcin in animal feed: is there a link? | journal = The Medical Journal of Australia | volume = 171 | issue = 3 | pages = 144–6 | date = August 1999 | pmid = 10474607 | doi = 10.5694/j.1326-5377.1999.tb123568.x | s2cid = 24378463 | author-link = Peter Collignon }}</ref><ref name="pmid17298380">{{cite journal | vauthors = Lauderdale TL, Shiau YR, Wang HY, Lai JF, Huang IW, Chen PC, Chen HY, Lai SS, Liu YF, Ho M | title = Effect of banning vancomycin analogue avoparcin on vancomycin-resistant enterococci in chicken farms in Taiwan | journal = Environmental Microbiology | volume = 9 | issue = 3 | pages = 819–23 | date = March 2007 | pmid = 17298380 | doi = 10.1111/j.1462-2920.2006.01189.x | bibcode = 2007EnvMi...9..819L | url = http://ir.nhri.org.tw/bitstream/3990099045/1956/1/000244078500024.pdf | access-date = 20 April 2018 | archive-date = 10 May 2019 | archive-url = https://web.archive.org/web/20190510090150/http://ir.nhri.org.tw/bitstream/3990099045/1956/1/000244078500024.pdf | url-status = live }}</ref>

One mechanism of resistance to vancomycin involves the alteration to the terminal amino acid residues of the [[N-Acetylmuramic acid|NAM]]/[[N-Acetylglucosamine|NAG]]-peptide subunits, under normal conditions, <small>D</small>-alanyl-<small>D</small>-alanine, to which vancomycin binds. The <small>D</small>-alanyl-<small>D</small>-lactate variation results in the loss of one hydrogen-bonding interaction (4, as opposed to 5 for <small>D</small>-alanyl-<small>D</small>-alanine) possible between vancomycin and the peptide. This loss of just one point of interaction results in a 1000-fold decrease in affinity. The <small>D</small>-alanyl-<small>D</small>-serine variation causes a six-fold loss of affinity between vancomycin and the peptide, likely due to [[steric hindrance]].<ref name="pmid11807177">{{cite journal | vauthors = Pootoolal J, Neu J, Wright GD | title = Glycopeptide antibiotic resistance | journal = Annual Review of Pharmacology and Toxicology | volume = 42 | pages = 381–408 | year = 2002 | pmid = 11807177 | doi = 10.1146/annurev.pharmtox.42.091601.142813 }}</ref>

In enterococci, this modification appears to be due to the expression of an enzyme that alters the terminal residue. Three main resistance variants have been characterised to date among resistant ''Enterococcus faecium'' and ''E. faecalis'' populations:
* VanA - enterococcal resistance to vancomycin and [[teicoplanin]]; inducible on exposure to these agents
* VanB - lower-level enterococcal resistance; inducible by vancomycin, but strains may remain susceptible to teicoplanin
* VanC - least clinically important; enterococci resistant only to vancomycin; constitutive resistance

A variant of vancomycin has been tested that binds to the resistant D-lactic acid variation in vancomycin-resistant bacterial cell walls and also binds well to the original target (vancomycin-susceptible bacteria).<ref name="pmid21823662">{{cite journal | vauthors = Xie J, Pierce JG, James RC, Okano A, Boger DL | title = A redesigned vancomycin engineered for dual D-Ala-D-ala And D-Ala-D-Lac binding exhibits potent antimicrobial activity against vancomycin-resistant bacteria | journal = Journal of the American Chemical Society | volume = 133 | issue = 35 | pages = 13946–9 | date = September 2011 | pmid = 21823662 | pmc = 3164945 | doi = 10.1021/ja207142h | bibcode = 2011JAChS.13313946X | author-link5 = Dale L. Boger }}</ref><ref name="pmid28559345">{{cite journal | vauthors = Okano A, Isley NA, Boger DL | title = Peripheral modifications of [Ψ[CH<sub>2</sub>NH]Tpg<sup>4</sup>]vancomycin with added synergistic mechanisms of action provide durable and potent antibiotics  | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 114 | issue = 26 | pages = E5052–E5061 | date = June 2017 | pmid = 28559345 | pmc = 5495262 | doi = 10.1073/pnas.1704125114 | author-link3 = Dale L. Boger | doi-access = free | bibcode = 2017PNAS..114E5052O }}</ref>