Editing Penicillin (section)

=== Mechanism of action ===
{{Main|Beta-lactam antibiotic}}
[[File:Penicillin spheroplast generation horizontal.svg|thumb|upright=2|Gram-negative bacteria that attempt to grow and divide in the presence of penicillin fail to do so, and instead end up shedding their cell walls.<ref name=":4" />]]
[[File:Penicillin inhibition.svg|thumb|upright=1.3|Penicillin and other β-lactam antibiotics act by inhibiting [[penicillin-binding proteins]], which normally catalyze cross-linking of bacterial cell walls.]]

Penicillin kills bacteria by inhibiting the completion of the synthesis of [[peptidoglycan]]s, the structural component of the [[bacterial cell wall]]. It specifically inhibits the activity of enzymes that are needed for the cross-linking of peptidoglycans during the final step in cell wall biosynthesis. It does this by binding to [[penicillin binding proteins]] with the β-lactam ring, a structure found on penicillin molecules.<ref>{{cite journal | vauthors = Yocum RR, Rasmussen JR, Strominger JL | title = The mechanism of action of penicillin. Penicillin acylates the active site of Bacillus stearothermophilus D-alanine carboxypeptidase | journal = The Journal of Biological Chemistry | volume = 255 | issue = 9 | pages = 3977–86 | date = May 1980 | pmid = 7372662 | doi = 10.1016/S0021-9258(19)85621-1 | doi-access = free }}</ref><ref>{{cite web|title=Benzylpenicillin|url=https://www.drugbank.ca/drugs/DB01053|access-date=22 January 2019|website=www.drugbank.ca|archive-date=23 January 2019|archive-url=https://web.archive.org/web/20190123071652/https://www.drugbank.ca/drugs/DB01053|url-status=live}}</ref> This causes the cell wall to weaken due to fewer cross-links and means water uncontrollably flows into the cell because it cannot maintain the correct osmotic gradient. This results in cell [[lysis]] and death.

Bacteria constantly remodel their peptidoglycan cell walls, simultaneously building and breaking down portions of the cell wall as they grow and divide. During the last stages of peptidoglycan biosynthesis, uridine diphosphate-''N''-acetylmuramic acid pentapeptide (UDP-MurNAc) is formed in which the fourth and fifth amino acids are both <small>D</small>-alanyl-<small>D</small>-alanine. The transfer of <small>D</small>-alanine is done (catalysed) by the [[enzyme]] [[DD-Transpeptidase|<small>DD</small>-transpeptidase]] ([[penicillin binding proteins|penicillin-binding proteins]] are such type).<ref name=":7"/> The structural integrity of bacterial cell wall depends on the [[Cross-link|cross linking]] of UDP-MurNAc and ''N''-acetyl glucosamine.<ref>{{cite journal | vauthors = DeMeester KE, Liang H, Jensen MR, Jones ZS, D'Ambrosio EA, Scinto SL, Zhou J, Grimes CL | title = Synthesis of Functionalized N-Acetyl Muramic Acids To Probe Bacterial Cell Wall Recycling and Biosynthesis | journal = Journal of the American Chemical Society | volume = 140 | issue = 30 | pages = 9458–65 | date = August 2018 | pmid = 29986130 | pmc = 6112571 | doi = 10.1021/jacs.8b03304 | bibcode = 2018JAChS.140.9458D }}</ref> Penicillin and other β-lactam antibiotics act as an analogue of <small>D</small>-alanine-<small>D</small>-alanine (the dipeptide) in UDP-MurNAc owing to conformational similarities. The <small>DD</small>-transpeptidase then binds the four-membered β-lactam [[cycloalkane|ring]] of penicillin instead of UDP-MurNAc.<ref name=":7" /> As a consequence, <small>DD</small>-transpeptidase is inactivated, the formation of cross-links between UDP-MurNAc and ''N''-acetyl glucosamine is blocked so that an imbalance between cell wall production and degradation develops, causing the cell to rapidly die.<ref name=":3">{{cite journal | vauthors = Gordon E, Mouz N, Duée E, Dideberg O | title = The crystal structure of the penicillin-binding protein 2x from Streptococcus pneumoniae and its acyl-enzyme form: implication in drug resistance | journal = Journal of Molecular Biology | volume = 299 | issue = 2 | pages = 477–85 | date = June 2000 | pmid = 10860753 | doi = 10.1006/jmbi.2000.3740 }}</ref>

The enzymes that [[hydrolyze]] the peptidoglycan cross-links continue to function, even while those that form such cross-links do not. This weakens the cell wall of the bacterium, and osmotic pressure becomes increasingly uncompensated—eventually causing cell death ([[cytolysis]]). In addition, the build-up of peptidoglycan precursors triggers the activation of bacterial cell wall hydrolases and autolysins, which further digest the cell wall's peptidoglycans. The small size of the penicillins increases their potency, by allowing them to penetrate the entire depth of the cell wall. This is in contrast to the [[glycopeptide antibiotics]] [[vancomycin]] and [[teicoplanin]], which are both much larger than the penicillins.<ref>{{cite book|vauthors=Van Bambeke F, Lambert D, Mingeot-Leclercq MP, Tulkens P|title=Mechanism of Action|date=1999|url=http://www.facm.ucl.ac.be/Full-texts-FACM/Vanbambeke-1999-3.pdf|access-date=2014-03-13|archive-date=2022-01-25|archive-url=https://web.archive.org/web/20220125025037/https://www.facm.ucl.ac.be/Full-texts-FACM/Vanbambeke-1999-3.pdf|url-status=live}}</ref>

Gram-positive bacteria are called [[protoplast]]s when they lose their cell walls. [[Gram-negative]] bacteria do not lose their cell walls completely and are called [[spheroplast]]s after treatment with penicillin.<ref name=":4">{{cite journal | vauthors = Cushnie TP, O'Driscoll NH, Lamb AJ | title = Morphological and ultrastructural changes in bacterial cells as an indicator of antibacterial mechanism of action | journal = Cellular and Molecular Life Sciences | volume = 73 | issue = 23 | pages = 4471–92 | date = December 2016 | pmid = 27392605 | doi = 10.1007/s00018-016-2302-2 | pmc = 11108400 | hdl = 10059/2129 | s2cid = 2065821 | url = https://zenodo.org/record/883501 | hdl-access = free | access-date = 2019-10-10 | archive-date = 2017-10-07 | archive-url = https://web.archive.org/web/20171007220157/https://zenodo.org/record/883501 | url-status = live }}</ref>

Penicillin shows a synergistic effect with [[aminoglycosides]], since the inhibition of peptidoglycan synthesis allows aminoglycosides to penetrate the bacterial cell wall more easily, allowing their disruption of bacterial protein synthesis within the cell. This results in a lowered [[Minimum Bactericidal Concentration|MBC]] for susceptible organisms.<ref>{{cite journal | vauthors = Winstanley TG, Hastings JG | title = Penicillin-aminoglycoside synergy and post-antibiotic effect for enterococci | journal = The Journal of Antimicrobial Chemotherapy | volume = 23 | issue = 2 | pages = 189–99 | date = February 1989 | pmid = 2708179 | doi = 10.1093/jac/23.2.189 }}</ref>

Penicillins, like other ''β''-lactam antibiotics, block not only the division of bacteria, including [[cyanobacteria]], but also the division of cyanelles, the [[Photosynthesis|photosynthetic]] [[organelle]]s of the [[glaucophyte]]s, and the division of [[chloroplast]]s of [[bryophyte]]s. In contrast, they have no effect on the [[plastid]]s of the highly developed [[vascular plant]]s. This supports the [[endosymbiotic theory]] of the [[evolution]] of plastid division in land plants.<ref>{{cite journal|vauthors=Kasten B, Reski R|author-link2=Ralf Reski|date=March 30, 1997|title=β-lactam antibiotics inhibit chloroplast division in a moss (Physcomitrella patens) but not in tomato (Lycopersicon esculentum)|journal=Journal of Plant Physiology|volume=150|pages=137–40|url=http://cat.inist.fr/?aModele=afficheN&cpsidt=2640663|issue=1–2|doi=10.1016/S0176-1617(97)80193-9|bibcode=1997JPPhy.150..137K |access-date=March 30, 2009|archive-date=July 21, 2011|archive-url=https://web.archive.org/web/20110721001848/http://cat.inist.fr/?aModele=afficheN&cpsidt=2640663|url-status=dead}}</ref>

Some bacteria produce enzymes that break down the β-lactam ring, called [[Beta-lactamase|β-lactamases]], which make the bacteria resistant to penicillin. Therefore, some penicillins are modified or given with other drugs for use against antibiotic-resistant bacteria or in immunocompromised patients. The use of clavulanic acid or tazobactam, β-lactamase inhibitors, alongside penicillin gives penicillin activity against β-lactamase-producing bacteria. β-Lactamase inhibitors irreversibly bind to β-lactamase preventing it from breaking down the beta-lactam rings on the antibiotic molecule. Alternatively, flucloxacillin is a modified penicillin that has activity against β-lactamase-producing bacteria due to an acyl side chain that protects the beta-lactam ring from β-lactamase.<ref name=":1" />