Meticillin

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Meticillin
Methicillin.svg
Systematic (IUPAC) name
(2S,5R,6R)-6-[(2,6-dimethoxybenzoyl)amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid
Clinical data
Legal status ?
Routes IV
Pharmacokinetic data
Bioavailability Not orally absorbed
Metabolism hepatic, 20–40%
Half-life 25–60 minutes
Excretion renal
Identifiers
CAS number 61-32-5 YesY
ATC code J01CF03 QJ51CF03
PubChem CID 6087
DrugBank DB01603
ChemSpider 5862 N
UNII Q91FH1328A N
ChEMBL CHEMBL575 N
Chemical data
Formula C17H20N2O6S 
Mol. mass 380.42 g/mol
 N (what is this?)  (verify)

Meticillin (INN, BAN) or methicillin (USAN) is a narrow-spectrum beta-lactam antibiotic of the penicillin class. It should not be confused with the antibiotic metacycline. In 2005 the name of the drug was changed from methicillin to meticillin in accordance with the International Pharmacopoeia guidelines.[1]

History[edit]

Meticillin was developed by Beecham in 1959.[2] It was previously used to treat infections caused by susceptible Gram-positive bacteria, in particular, beta-lactamase-producing organisms such as Staphylococcus aureus that would otherwise be resistant to most penicillins, but it is no longer clinically used.[clarification needed]

Its role in therapy has been largely replaced by flucloxacillin and dicloxacillin, however the term meticillin-resistant Staphylococcus aureus (MRSA) continues to be used to describe Staphylococcus aureus strains resistant to all penicillins.[3]

Meticillin is no longer manufactured because the more stable and similar penicillins such as oxacillin (used for clinical antimicrobial susceptibility testing), flucloxacillin, and dicloxacillin are used medically.

Mode of action[edit]

Like other beta-lactam antibiotics, meticillin acts by inhibiting the synthesis of bacterial cell walls. 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 transpeptidase enzyme used by bacteria to cross-link the peptide (D-alanyl-alanine) used in peptidoglycan synthesis. Meticillin and other beta-lactam antibiotics are structural analogs of D-alanyl-alanine, and the transpeptidase enzymes that bind to them are sometimes called penicillin-binding proteins (PBPs).[4]

Spectrum of bacterial resistance and susceptibility[edit]

At one time, methicillin was used to treat infections caused by certain Gram-positive bacteria including Staphylcoccus aureus, Staphylococcus epidermidis, Streptococcus pyogenes, and Streptococcus pneumoniae. Today, methicillin is not as effective against these organisms due to increasing resistance. The following provides susceptibility data on a few medically significant bacteria:

  • Staphylococcus aureus - 0.125 μg/mL - >100 μg/mL
  • Methicillin resistant Staphylococcus aureus (MRSA) - 15.6 μg/mL - >1000 μg/mL
  • Streptococcus pneumoniae 0.39 μg/mL

[5]

Medicinal chemistry[edit]

Meticillin is insensitive to beta-lactamase (also known as penicillinase) enzymes secreted by many penicillin-resistant bacteria. The presence of the ortho-dimethoxyphenyl group directly attached to the 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 penicillin-binding proteins (PBPs) and inhibit peptidoglycan crosslinking, but it is not bound by or inactivated by β-lactamases.

Clinical use[edit]

Meticillin is no longer used to treat patients. Compared to other beta-lactamase-resistant penicillins, it is less active, can be administered only parenterally, and has a higher frequency of interstitial nephritis, an otherwise-rare side-effect of penicillins. However, it serves a purpose in the laboratory to determine the antibiotic sensitivity of Staphylococcus aureus to other beta-lactamase-resistant penicillins.

References[edit]

  1. ^ UK parliament MRSA
  2. ^ Graham Dutfield (30 July 2009). Intellectual property rights and the life science industries: past, present and future. World Scientific. pp. 140–. ISBN 978-981-283-227-6. Retrieved 18 November 2010. 
  3. ^ MRSA—past, present, future
  4. ^ Gladwin M., Trattler B. Clinical Microbiology made ridiculously simple. 3rd edition. Miami: MedMaster, Inc.; 2004.
  5. ^ http://www.toku-e.com/Assets/MIC/Methicillin%20sodium.pdf