methicillin

Meticillin
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
Identifiers
CAS number	61-32-5
ATC code	J01CF03 QJ51CF03
PubChem	6087
Chemical data
Formula	C17H20N2O6S
Mol. mass	380.42 g/mol
SMILES	eMolecules & PubChem
Pharmacokinetic data
Bioavailability	Not orally absorbed
Metabolism	hepatic, 20–40%
Half life	25–60 minutes
Excretion	renal
Therapeutic considerations
Pregnancy cat.	?
Legal status
Routes	IV

Meticillin (INN, BAN) or methicillin (USAN) is a narrow spectrum beta-lactam antibiotic of the penicillin class. It was developed by Beecham in 1959. It was previously used to treat infections caused by susceptible Gram-positive bacteria, particularly beta-lactamase-producing organisms such as Staphylococcus aureus that would otherwise be resistant to most penicillins, but is no longer clinically used. Its role in therapy has been largely replaced by flucloxacillin and dicloxacillin, however the term methicillin-resistant Staphylococcus aureus (MRSA) continues to be used to describe Staphylococcus aureus strains resistant to all penicillins. Methicillin 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

Like other beta-lactam antibiotics, methicillin 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. Methicillin 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). (Gladwin and Trattler, 2004)

Medicinal chemistry

Methicillin 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 is not bound by or inactivated by β-lactamases.

Clinical use

Methicillin is not used to treat patients because of its unfavorable side effect profile. But, it serves a purpose in the laboratory to determine the antibiotic sensitivity of Staph aureus to other beta-lactamase-resistant penicillins.

See also

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• Beta-lactam antibiotic
• Flucloxacillin
• Methicillin-resistant Staphylococcus aureus

References

• Mitscher LA. Antibiotics and antimicrobial agents. In: Williams DA, Lemke TL, editors. Foye's Principles of medicinal chemistry, 5th edition. Philadelphia: Lippincott Williams & Wilkins; 2002.
• Gladwin M., Trattler B. Clinical Microbiology made ridiculously simple. 3rd edition. Miami: MedMaster, Inc.; 2004.