Editing Vancomycin (section)

== Mechanism of action ==
[[Image:Vancomysin AntimicrobAgentsChemother 1990 1342 commons.jpg|thumbnail|Crystal structure of a short peptide <small>L</small>-Lys-<small>D</small>-Ala-<small>D</small>-Ala (bacterial cell wall precursor, in green) bound to vancomycin (blue) through [[hydrogen bond]]s<ref name="pmid2386365">{{cite journal | vauthors = Knox JR, Pratt RF | title = Different modes of vancomycin and D-alanyl-D-alanine peptidase binding to cell wall peptide and a possible role for the vancomycin resistance protein | journal = Antimicrobial Agents and Chemotherapy | volume = 34 | issue = 7 | pages = 1342–7 | date = July 1990 | pmid = 2386365 | pmc = 175978 | doi = 10.1128/AAC.34.7.1342 }}</ref>]]
Vancomycin targets bacterial cell wall synthesis by binding to the basic building block of the bacterial cell wall of Gram-positive bacteria, whether it is of [[Aerobic bacteria|aerobic]] or [[Anaerobic bacteria|anaerobic]] type.<ref name="B978"/> Specifically, vancomycin forms hydrogen bonds with the <small>D</small>-alanyl-<small>D</small>-alanine (<small>D</small>-Ala-<small>D</small>-Ala) peptide motif of the peptidoglycan precursor, a component of the bacterial cell wall.<ref name="pmid31545906"/>

Peptidoglycan is a polymer that provides structural support to the bacterial cell wall. The peptidoglycan precursor is synthesized in the cytoplasm and then transported across the cytoplasmic membrane to the periplasmic space, where it is assembled into the cell wall. The assembly process involves two enzymatic activities: transglycosylation and transpeptidation. Transglycosylation involves the polymerization of the peptidoglycan precursor into long chains, while transpeptidation involves the cross-linking of these chains to form a three-dimensional mesh-like structure.<ref name="pmid31545906"/>

Vancomycin inhibits bacterial cell wall synthesis by binding to the <small>D</small>-Ala-<small>D</small>-Ala peptide motif of the peptidoglycan precursor, thereby preventing its processing by the transglycosylase; as such, vancomycin disrupts the transglycosylation activity of the cell wall synthesis process. The disruption leads to an incomplete and corrupted cell wall, which makes the replicating bacteria vulnerable to external forces such as osmotic pressure, so that the bacteria cannot survive and are eliminated by the immune system.<ref name="pmid31545906"/>

Gram-negative bacteria are insensitive to vancomycin due to their different cell wall morphology. The outer membrane of Gram-negative bacteria contains lipopolysaccharide, which acts as a barrier to vancomycin penetration. That is why vancomycin is mainly used to treat infections caused by Gram-positive bacteria<ref name="pmid31545906"/> (except some nongonococcal species of ''[[Neisseria]]'').<ref name="pmid30408494">{{cite journal |vauthors=Crew PE, McNamara L, Waldron PE, McCulley L, Jones SC, Bersoff-Matcha SJ |title=Unusual Neisseria species as a cause of infection in patients taking eculizumab |journal=J Infect |volume=78 |issue=2 |pages=113–118 |date=February 2019 |pmid=30408494 |pmc=7224403 |doi=10.1016/j.jinf.2018.10.015 }}</ref><ref name="pmid6790572">{{cite journal |vauthors=Mirrett S, Reller LB, Knapp JS |title=Neisseria gonorrhoeae strains inhibited by vancomycin in selective media and correlation with auxotype |journal=J Clin Microbiol |volume=14 |issue=1 |pages=94–9 |date=July 1981 |pmid=6790572 |pmc=271907 |doi=10.1128/jcm.14.1.94-99.1981}}</ref>

The large [[hydrophilic]] molecule of vancomycin is able to form [[hydrogen bond]] interactions with the terminal <small>D</small>-alanyl-<small>D</small>-alanine moieties of the NAM/NAG-peptides. Under normal circumstances, this is a five-point interaction. This binding of vancomycin to the <small>D</small>-Ala-<small>D</small>-Ala prevents cell wall synthesis of the long polymers of ''N''-acetylmuramic acid (NAM) and ''N''-acetylglucosamine (NAG) that form the backbone strands of the bacterial cell wall, and prevents the backbone polymers  from cross-linking with each other.<ref name="Clinical-Pharmacology-2021">{{cite web |url=http://www.clinicalpharmacology-ip.com/Forms/Monograph/monograph.aspx?cpnum=638&sec=monmech |title=Clinical Pharmacology<!-- Bot generated title --> |access-date=10 September 2011 |archive-date=27 August 2021 |archive-url=https://web.archive.org/web/20210827175717/http://www.clinicalpharmacology-ip.com/Forms/login.aspx?ReturnUrl=%2fForms%2fMonograph%2fmonograph.aspx%3fcpnum%3d638%26sec%3dmonmech&cpnum=638&sec=monmech |url-status=dead }}</ref>

{{wide image|Vancomycin resistance.svg|800px|
Mechanism of vancomycin action and resistance: This diagram shows only one of two ways vancomycin acts against bacteria (inhibition of cell wall cross-linking) and only one of many ways that bacteria can become resistant to it.
# Vancomycin is added to the bacterial environment while it is trying to synthesize new cell wall. Here, the cell wall strands have been synthesized, but not yet cross-linked.
# Vancomycin recognizes and binds to the two <small>D</small>-ala residues on the end of the peptide chains. However, in resistant bacteria, the last <small>D</small>-ala residue has been replaced by a <small>D</small>-lactate, so vancomycin cannot bind.
# In the resistant bacteria, cross-links are successfully formed; still, in the nonresistant (sensitive) bacteria, the vancomycin bound to the peptide chains prevents them from interacting properly with the cell wall cross-linking enzyme.
# In the resistant bacteria, stable cross-links are formed. In the sensitive bacteria, cross-links cannot be formed and the cell wall falls apart.
}}