Meticillin

Meticillin

Systematic (IUPAC) name
(2S,5R,6R)-6-(2,6-dimethoxybenzamido)-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid
Clinical data
Routes of administration	IV
Pharmacokinetic data
Bioavailability	Not orally absorbed
Metabolism	hepatic, 20–40%
Biological half-life	25–60 minutes
Excretion	renal
Identifiers
CAS Number	61-32-5 Y
ATC code	J01CF03 (WHO) QJ51CF03 (WHO)
PubChem	CID: 6087
DrugBank	DB01603 Y
ChemSpider	5862 N
UNII	Q91FH1328A N
ChEMBL	CHEMBL575 N
Chemical data
Formula	C17H20N2O6S
Molecular mass	380.42 g/mol
SMILES OC(=O)[C@@H]2N3C(=O)[C@@H](NC(=O)c1c(OC)cccc1OC)[C@H]3SC2(C)C
NY (what is this?)  (verify)

Meticillin (INN, BAN) or methicillin (USAN, AAN) is a narrow-spectrum β-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.

Medical uses

Meticillin is no longer used to treat patients. Compared to other β-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, selection of Meticillin depended on the outcome of susceptibility test of the microorganism, since it is no longer produced, it is also not routinely tested any more. It also served a purpose in the laboratory to determine the antibiotic sensitivity of Staphylococcus aureus to other β-lactamase-resistant penicillins; this role has now been passed on to other penicillines, namely Cloxacillin as well as genetic testing for the presence of mecA gene by PCR.

Spectrum of activity

At one time, meticillin was used to treat infections caused by certain Gram-positive bacteria including Staphylococcus aureus, Staphylococcus epidermidis, Streptococcus pyogenes, and Streptococcus pneumoniae. Today, meticillin is not as effective against these organisms due to resistance.

Resistance to meticillin is conferred by activation of a new bacterial PBP gene (mecA). 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. Expression of PBPA2 confers resistance to all β-lactams.

These susceptibility data are given on a few medically significant bacteria:

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

Mechanism of action

Main article: β-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 (also known as penicillin-binding proteins (PBPs)). These PBPs crosslink glycopeptides (D-alanyl-alanine), forming the peptidoglycan cell wall. Meticillin and other β-lactam antibiotics are structural analogs of D-alanyl-alanine, and the transpeptidase enzymes that bind to them are sometimes called penicillin-binding proteins (PBPs).

Meticillin is actually a penicillinase-resistant B-lactam antibiotic. Penicillinase is a bacterial enzyme produced by bacteria resistant to other B-lactam antibiotics which hydrolyses the antibiotic, rendering it nonfunctional. Meticillin is not bound and hydrolysed by penicillinase, meaning it can kill the bacteria, even if this enzyme is present.

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 PBPs and inhibit peptidoglycan crosslinking, but it is not bound by or inactivated by β-lactamases.

History

Meticillin was developed by Beecham in 1959. It was previously used to treat infections 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 flucloxacillin and dicloxacillin, but the term meticillin-resistant Staphylococcus aureus (MRSA) continues to be used to describe S. aureus strains resistant to all penicillins.

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.