Editing Methicillin

{{Short description|Antibiotic medication}}
{{distinguish|metacycline}}

{{drugbox

| INN            = Meticillin
| Verifiedfields = changed
| Watchedfields = changed
| verifiedrevid = 404016571
| IUPAC_name = (2''S'',5''R'',6''R'')-6-(2,6-dimethoxybenzamido)-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid
| image = Methicillin.svg
| image2 = Methicillin-based-on-xtal-3D-bs-17.png
<!--Clinical data-->
| pregnancy_AU = <!-- A / B1 / B2 / B3 / C / D / X -->
| pregnancy_US = <!-- A / B / C / D / X -->
| legal_AU = <!-- Unscheduled / S2 / S3 / S4 / S5 / S6 / S7 / S8 / S9 -->
| legal_CA = <!-- / Schedule I, II, III, IV, V, VI, VII, VIII -->
| legal_UK = <!-- GSL / P / POM / CD / Class A, B, C -->
| legal_US = <!-- OTC / Rx-only / Schedule I, II, III, IV, V -->
| routes_of_administration = [[Intravenous|IV]]
<!--Pharmacokinetic data-->
| bioavailability = Not orally absorbed
| metabolism = hepatic, 20–40%
| elimination_half-life = 25–60 minutes
| excretion = renal
<!--Identifiers-->
| CAS_number_Ref = {{cascite|correct|??}}
| CAS_number = 61-32-5
| ATC_prefix = J01
| ATC_suffix = CF03
| ATC_supplemental =  {{ATCvet|J51|CF03}}
| PubChem = 6087
| DrugBank_Ref = {{drugbankcite|correct|drugbank}}
| DrugBank = DB01603
| ChemSpiderID_Ref = {{chemspidercite|changed|chemspider}}
| ChemSpiderID = 5862
| UNII_Ref = {{fdacite|changed|FDA}}
| UNII = Q91FH1328A
| ChEMBL_Ref = {{ebicite|changed|EBI}}
| ChEMBL = 575
<!--Chemical data-->
| C=17 | H=20 | N=2 | O=6 | S=1
| smiles = OC(=O)[C@@H]2N3C(=O)[C@@H](NC(=O)c1c(OC)cccc1OC)[C@H]3SC2(C)C
}}
'''Methicillin''' ([[United States Adopted Name|USAN]]), also known as '''meticillin''' ([[international nonproprietary name|INN]]), is a [[narrow-spectrum antibiotic|narrow-spectrum]] [[β-lactam antibiotic]] of the [[penicillin]] class.
<!--Wikipedia is supposed to have a rule about medication articles residing at the page title for the INN, not at the non-INN name such as USAN (for drugs for which that name differs anyway/at all), but most people are too ignorant even to know how to look up in non-erroneous databases what the real INN actually is, as opposed to what google erroneously told them it is based on what various random garbage websites mistakenly claim that it is because they are made by lazy/ignorant content-farmers.-->

<!-- History -->
Methicillin was discovered in 1960.<ref name=Wal2012>{{cite book| vauthors = Walker SR |title=Trends and Changes in Drug Research and Development |date=2012 |publisher=Springer Science & Business Media |isbn=9789400926592 |page=109 |url= https://books.google.com/books?id=FB_2CAAAQBAJ&pg=PA109 }}</ref>

== Medical uses ==

Compared to other penicillins that face [[antimicrobial resistance]] due to [[beta-lactamase|β-lactamase]], it is less active, can be administered only [[Route of administration#Parenteral|parenterally]], and has a higher frequency of [[interstitial nephritis]], an otherwise-rare [[adverse effect]] of penicillins. However, selection of methicillin depended on the outcome of [[antibiotic sensitivity|susceptibility testing]] of the sampled infection, and since it is no longer produced, it is also not routinely tested for any more. It also served a purpose in the [[laboratory]] to determine the antibiotic sensitivity of ''[[Staphylococcus aureus]]'' to other penicillins facing β-lactam resistance; this role has now been passed on to other penicillins, namely ''[[cloxacillin]]'', as well as [[genetic testing]] for the presence of ''[[mecA]]'' gene by ''[[Polymerase chain reaction|PCR]]''.{{cn|date=March 2023}}

=== Spectrum of activity ===
At one time, methicillin was used to treat infections caused by certain [[gram-positive bacteria]] including ''Staphylococcus aureus'', ''Staphylococcus epidermidis'', ''Streptococcus pyogenes'', and ''Streptococcus pneumoniae''. Methicillin is only effective against ''Staphylococcus aureus'' 50% of the time.

Resistance to methicillin is conferred by activation of a new bacterial [[penicillin binding protein]] (PBP) ''[[mecA (gene)|mecA gene]]''. This encodes protein PBP2a. PBP2a works in a similar manner to other PBPs, but it binds β-lactams with very low affinity, meaning they do not compete efficiently with the natural substrate of the enzyme and will not inhibit cell wall biosynthesis.

These susceptibility data are given on a few medically significant bacteria:
* ''Staphylococcus aureus'': 0.125 – >100&nbsp;μg/ml
* [[Methicillin resistant Staphylococcus aureus]] (MRSA): 15.6 – >1000&nbsp;μg/ml
* ''Streptococcus pneumoniae'': 0.39&nbsp;μg/ml<ref>{{cite web | title = Methicillin Sodium Susceptibility and Concentration (MIC) Data | url = http://www.toku-e.com/Assets/MIC/Methicillin%20sodium.pdf | work = TOKU-E }}</ref>

== Mechanism of action ==

{{main|β-Lactam antibiotic}}

Like other beta-lactam antibiotics, methicillin acts by inhibiting the synthesis of bacterial [[cell wall]]s. It inhibits cross-linkage between the linear [[peptidoglycan]] polymer chains that make up a major component of the cell wall of gram-positive bacteria. It does this by binding to and competitively inhibiting the [[DD-Transpeptidase|transpeptidase]] enzyme (also known as [[penicillin-binding proteins]] (PBPs)). These PBPs crosslink glycopeptides (''<small>D</small>-alanyl-alanine''), forming the peptidoglycan cell wall. Methicillin and other β-lactam antibiotics are structural analogs of <small>D</small>-alanyl-alanine, and the transpeptidase enzymes that bind to them are sometimes called [[penicillin-binding proteins]] (PBPs).<ref>{{cite book | vauthors = Gladwin M, Trattler B | title = Clinical Microbiology made ridiculously simple | edition = 3rd | location = Miami | publisher = MedMaster, Inc. | date = 2004 }}</ref>

Methicillin is actually a [[penicillinase]]-resistant β-lactam antibiotic. Penicillinase is a bacterial enzyme produced by bacteria resistant to other β-lactam antibiotics which hydrolyses the antibiotic, rendering it non-functional. Methicillin is not bound and hydrolysed by penicillinase, meaning it can kill the bacteria, even if this enzyme is present.

== Medicinal chemistry ==

Methicillin is resistant to [[beta-lactamase]]s, which are enzymes secreted by many beta-lactam antibiotic-resistant bacteria. The presence of the {{nobr|''ortho''-dimethoxyphenyl group}} directly attached to the [[Side chain|side-chain]] carbonyl group of the penicillin nucleus facilitates the β-lactamase  resistance, since those enzymes are relatively intolerant of side-chain [[steric hindrance]]. Thus, it is able to bind to PBPs and inhibit [[peptidoglycan]] crosslinking, but it is not bound by nor inactivated by β-lactamases.{{cn|date=March 2023}}

==History==
Methicillin was developed by [[Beecham (pharmaceutical company)|Beecham]] in 1959.<ref name="Dutfield2009">{{cite book| first = Graham | last = Dutfield | name-list-style = vanc |title=Intellectual property rights and the life science industries: past, present and future|url=https://books.google.com/books?id=hnleY38aUxYC&pg=PA140|access-date=18 November 2010|date=30 July 2009|publisher=World Scientific|isbn=978-981-283-227-6|pages=140–}}</ref> It was previously used to treat [[infection]]s caused by susceptible gram-positive bacteria, in particular, [[penicillinase]]-producing organisms such as ''[[Staphylococcus aureus]]'' that would otherwise be resistant to most penicillins.

Its role in therapy has been largely replaced by [[oxacillin]] (used for clinical antimicrobial susceptibility testing), [[flucloxacillin]] and [[dicloxacillin]], but the term [[methicillin-resistant Staphylococcus aureus]] (MRSA) continues to be used to describe ''S. aureus'' strains resistant to all penicillins.<ref>{{cite journal | vauthors = Newsom SW | title = MRSA--past, present, future | journal = Journal of the Royal Society of Medicine | volume = 97 | issue = 11 | pages = 509–10 | date = November 2004 | pmid = 15520143 | pmc = 1079642 | doi = 10.1177/014107680409701101 }}</ref>

== References ==
{{reflist}}
{{wikinews|Supergerm deaths soar, surpass AIDS in the United States}}

{{Cell wall disruptive antibiotics}}

[[Category:Penicillins]]
[[Category:Benzamides]]
[[Category:Phenol ethers]]