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| Clinical data | |
|---|---|
| Routes of administration | IV |
| ATC code | |
| Pharmacokinetic data | |
| Bioavailability | Not orally absorbed |
| Metabolism | hepatic, 20–40% |
| Eliminationhalf-life | 25–60 minutes |
| Excretion | renal |
| Identifiers | |
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| CAS Number |
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| PubChemCID | |
| DrugBank |
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| ChemSpider |
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| UNII | |
| ChEMBL | |
| CompTox Dashboard(EPA) | |
| ECHA InfoCard | 100.000.460 |
| Chemical and physical data | |
| Formula | C17H20N2O6S |
| Molar mass | 380.42 g·mol−1 |
| 3D model (JSmol) | |
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 N Y (what is this?) (verify) | |
Methicillin (USAN), also known asmeticillin (INN), is anarrow-spectrumβ-lactam antibiotic of thepenicillin class.
Methicillin was discovered in 1960.[1]
Compared to other penicillins that faceantimicrobial resistance due toβ-lactamase, it is less active, can be administered onlyparenterally, and has a higher frequency ofinterstitial nephritis, an otherwise-rareadverse effect of penicillins. However, selection of methicillin depended on the outcome ofsusceptibility 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 thelaboratory to determine the antibiotic sensitivity ofStaphylococcus aureus to other penicillins facing β-lactam resistance; this role has now been passed on to other penicillins, namelycloxacillin, as well asgenetic testing for the presence ofmecA gene byPCR.[citation needed]
At one time, methicillin was used to treat infections caused by certaingram-positive bacteria includingStaphylococcus aureus,Staphylococcus epidermidis,Streptococcus pyogenes, andStreptococcus pneumoniae. Methicillin is only effective againstStaphylococcus aureus 50% of the time.
Resistance to methicillin is conferred by activation of a new bacterialpenicillin binding protein (PBP)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:
Like other beta-lactam antibiotics, methicillin acts by inhibiting the synthesis of bacterialcell walls. It inhibits cross-linkage between the linearpeptidoglycan 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 thetranspeptidase enzyme (also known aspenicillin-binding proteins (PBPs)). These PBPs crosslink glycopeptides (D-alanyl-alanine), forming the peptidoglycan cell wall. Methicillin and other β-lactam antibiotics are structural analogs ofD-alanyl-alanine, and the transpeptidase enzymes that bind to them are sometimes calledpenicillin-binding proteins (PBPs).[3]
Methicillin is actually apenicillinase-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.
Methicillin is resistant tobeta-lactamases, which are enzymes secreted by many beta-lactam antibiotic-resistant bacteria. The presence of theortho-dimethoxyphenyl group directly attached to theside-chain carbonyl group of the penicillin nucleus facilitates the β-lactamase resistance, since those enzymes are relatively intolerant of side-chainsteric hindrance. Thus, it is able to bind to PBPs and inhibitpeptidoglycan crosslinking, but it is not bound by nor inactivated by β-lactamases.[citation needed]
Methicillin was developed byBeecham in 1959.[4] It was previously used to treatinfections caused by susceptible gram-positive bacteria, in particular,penicillinase-producing organisms such asStaphylococcus aureus that would otherwise be resistant to most penicillins.
Its role in therapy has been largely replaced byoxacillin (used for clinical antimicrobial susceptibility testing),flucloxacillin anddicloxacillin, but the termmethicillin-resistant Staphylococcus aureus (MRSA) continues to be used to describeS. aureus strains resistant to all penicillins.[5]
