Methicillin

Methicillin

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

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.

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

Main article: Beta-lactam antibiotic

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]

Medicinal chemistry

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

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