Editing Penicillin (section)

== Resistance ==
When Alexander Fleming discovered the crude penicillin in 1928, one important observation he made was that many bacteria were not affected by penicillin.<ref name="Fleming1929" /> This phenomenon was realised by [[Ernst Chain]] and [[Edward Abraham]] while trying to identify the exact of penicillin. In 1940, they discovered that unsusceptible bacteria like ''[[Escherichia coli]]'' produced specific enzymes that can break down penicillin molecules, thus making them resistant to the antibiotic. They named the enzyme [[penicillinase]].<ref name=":14">{{cite journal | vauthors = Abraham EP, Chain E | title = An enzyme from bacteria able to destroy penicillin. 1940 | journal = Reviews of Infectious Diseases | volume = 10 | issue = 4 | pages = 677–78 | date = 1940 | pmid = 3055168 | doi = 10.1038/146837a0 | s2cid = 4070796 | bibcode = 1940Natur.146..837A | doi-access = free }}</ref> Penicillinase is now classified as member of enzymes called β-lactamases. These β-lactamases are naturally present in many other bacteria, and many bacteria produce them upon constant exposure to antibiotics. In most bacteria, resistance can be through three different mechanisms&nbsp;– reduced permeability in bacteria, reduced binding affinity of the penicillin-binding proteins (PBPs) or destruction of the antibiotic through the expression of β-lactamase.<ref>{{cite journal | vauthors = Rice LB | title = Mechanisms of resistance and clinical relevance of resistance to β-lactams, glycopeptides, and fluoroquinolones | journal = Mayo Clinic Proceedings | volume = 87 | issue = 2 | pages = 198–208 | date = February 2012 | pmid = 22305032 | pmc = 3498059 | doi = 10.1016/j.mayocp.2011.12.003 }}</ref> Using any of these, bacteria commonly develop resistance to different antibiotics, a phenomenon called [[multi-drug resistance]].

The actual process of resistance mechanism can be very complex. In case of reduced permeability in bacteria, the mechanisms are different between Gram-positive and Gram-negative bacteria. In Gram-positive bacteria, blockage of penicillin is due to changes in the cell wall. For example, resistance to vancomycin in ''S. aureus'' is due to additional peptidoglycan synthesis that makes the cell wall much thicker preventing effective penicillin entry.<ref name=":8" /> Resistance in Gram-negative bacteria is due to mutational variations in the structure and number of porins.<ref name=":11" /> In bacteria like ''Pseudomonas aeruginosa'', there is reduced number of porins; whereas in bacteria like ''Enterobacter'' species, ''Escherichia'' ''coli'' and ''Klebsiella pneumoniae'', there are modified porins such as non-specific porins (such as OmpC and OmpF groups) that cannot transport penicillin.<ref>{{cite journal |vauthors=Pagès JM, James CE, Winterhalter M |date=December 2008 |title=The porin and the permeating antibiotic: a selective diffusion barrier in Gram-negative bacteria |url=https://www.nature.com/articles/nrmicro1994 |url-status=live |journal=Nature Reviews. Microbiology |volume=6 |issue=12 |pages=893–903 |doi=10.1038/nrmicro1994 |pmid=18997824 |s2cid=6969441 |archive-url=https://salford-repository.worktribe.com/output/1430863/the-porin-and-the-permeating-antibiotic-a-selective-diffusion-barrier-in-gram-negative-bacteria |archive-date=31 May 2013 |access-date=10 December 2024}}</ref>

Resistance due to PBP alterations is highly varied. A common case is found in ''Streptococcus pneumoniae'' where there is mutation in the gene for PBP, and the mutant PBPs have decreased binding affinity for penicillins.<ref>{{cite journal | vauthors = Jacobs MR | title = Drug-resistant Streptococcus pneumoniae: rational antibiotic choices | journal = The American Journal of Medicine | volume = 106 | issue = 5A | pages = 19S–25S; discussion 48S–52S | date = May 1999 | pmid = 10348060 | doi = 10.1016/s0002-9343(98)00351-9 }}</ref> There are six mutant PBPs in ''S. pneumoniae'', of which PBP1a, PBP2b, PBP2x and sometimes PBP2a are responsible for reduced binding affinity.<ref name=":13" /> ''S. aureus'' can activate a hidden gene that produces a different PBP, PBD2, which has low binding affinity for penicillins.<ref>{{cite journal | vauthors = Peacock SJ, Paterson GK | title = Mechanisms of Methicillin Resistance in Staphylococcus aureus | journal = Annual Review of Biochemistry | volume = 84 | pages = 577–601 | date = 2015 | pmid = 26034890 | doi = 10.1146/annurev-biochem-060614-034516 | url = https://www.repository.cam.ac.uk/bitstream/1810/254765/1/HEFCE%20Exception%20sheet.pdf }}</ref> There is a different strain of ''S. aureus'' named [[Methicillin-resistant S. aureus|methicillin-resistant ''S. aureus'']] (MRSA) which is resistant not only to penicillin and other β-lactams, but also to most antibiotics. The bacterial strain developed after introduction of methicillin in 1959.<ref name=":9" /> In MRSA, mutations in the genes (''mec'' system) for PBP produce a variant protein called PBP2a (also termed PBP2'),<ref>{{cite journal | vauthors = Reygaert W | title = Methicillin-resistant Staphylococcus aureus (MRSA): molecular aspects of antimicrobial resistance and virulence | journal = Clinical Laboratory Science | volume = 22 | issue = 2 | pages = 115–19 | date = 2009 | pmid = 19534446 | url = https://pubmed.ncbi.nlm.nih.gov/19534446 | access-date = 2021-01-08 | archive-date = 2021-01-12 | archive-url = https://web.archive.org/web/20210112052544/https://pubmed.ncbi.nlm.nih.gov/19534446/ | url-status = live }}</ref> while making four normal PBPs. PBP2a has poor binding affinity for penicillin and also lacks glycosyltransferase activity required for complete peptidoglycan synthesis (which is carried out by the four normal PBPs).<ref name=":13">{{cite journal | vauthors = Zapun A, Contreras-Martel C, Vernet T | title = Penicillin-binding proteins and beta-lactam resistance | journal = FEMS Microbiology Reviews | volume = 32 | issue = 2 | pages = 361–85 | date = March 2008 | pmid = 18248419 | doi = 10.1111/j.1574-6976.2007.00095.x | doi-access = free }}</ref> In ''Helicobacter cinaedi'', there are multiple mutations in different genes that make PBP variants.<ref>{{cite journal | vauthors = Rimbara E, Mori S, Kim H, Suzuki M, Shibayama K | title = Mutations in Genes Encoding Penicillin-Binding Proteins and Efflux Pumps Play a Role in β-Lactam Resistance in Helicobacter cinaedi | journal = Antimicrobial Agents and Chemotherapy | volume = 62 | issue = 2 | pages = e02036-17 | date = February 2018 | pmid = 29203490 | pmc = 5786776 | doi = 10.1128/AAC.02036-17 }}</ref>

Enzymatic destruction by β-lactamases is the most important mechanism of penicillin resistance,<ref>{{cite journal | vauthors = Tooke CL, Hinchliffe P, Bragginton EC, Colenso CK, Hirvonen VH, Takebayashi Y, Spencer J | title = β-Lactamases and β-Lactamase Inhibitors in the 21st Century | journal = Journal of Molecular Biology | volume = 431 | issue = 18 | pages = 3472–3500 | date = August 2019 | pmid = 30959050 | pmc = 6723624 | doi = 10.1016/j.jmb.2019.04.002 }}</ref> and is described as "the greatest threat to the usage [of penicillins]".<ref name=":15">{{cite journal | vauthors = Bonomo RA | title = β-Lactamases: A Focus on Current Challenges | journal = Cold Spring Harbor Perspectives in Medicine | volume = 7 | issue = 1 | pages = a025239 | date = January 2017 | pmid = 27742735 | pmc = 5204326 | doi = 10.1101/cshperspect.a025239 }}</ref> It was the first discovered mechanism of penicillin resistance. During the experiments when purification and biological activity tests of penicillin were performed in 1940, it was found that ''E. coli'' was unsusceptible.<ref name="Davies">{{cite journal | vauthors = Davies J, Davies D | title = Origins and evolution of antibiotic resistance | journal = Microbiology and Molecular Biology Reviews | volume = 74 | issue = 3 | pages = 417–33 | date = September 2010 | pmid = 20805405 | pmc = 2937522 | doi = 10.1128/MMBR.00016-10 }}</ref> The reason was discovered as production of an enzyme penicillinase (hence, the first β-lactamase known) in ''E. coli'' that easily degraded penicillin.<ref name=":14" /> There are over 2,000 types of β-lactamases each of which has unique amino acid sequence, and thus, enzymatic activity.<ref name=":15" /> All of them are able to hydrolyse β-lactam rings but their exact target sites are different.<ref>{{cite journal | vauthors = Bush K | title = Past and Present Perspectives on β-Lactamases | journal = Antimicrobial Agents and Chemotherapy | volume = 62 | issue = 10 | pages = e01076-18 | date = October 2018 | pmid = 30061284 | pmc = 6153792 | doi = 10.1128/AAC.01076-18 }}</ref> They are secreted on the bacterial surface in large quantities in Gram-positive bacteria but less so in Gram-negative species. Therefore, in a mixed bacterial infection, the Gram-positive bacteria can protect the otherwise penicillin-susceptible Gram-negative cells.<ref name=":7" />

There are unusual mechanisms in ''P. aeruginosa'', in which there can be biofilm-mediated resistance and formation of multidrug-tolerant [[persister cells]].<ref>{{cite journal | vauthors = Pang Z, Raudonis R, Glick BR, Lin TJ, Cheng Z | title = Antibiotic resistance in Pseudomonas aeruginosa: mechanisms and alternative therapeutic strategies | journal = Biotechnology Advances | volume = 37 | issue = 1 | pages = 177–92 | date = 2019 | pmid = 30500353 | doi = 10.1016/j.biotechadv.2018.11.013 | doi-access = free }}</ref>