Methicillin

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Methicillin
INN: Meticillin
QJ51CF03 (WHO)
Pharmacokinetic data
BioavailabilityNot orally absorbed
Metabolismhepatic, 20–40%
Elimination half-life25–60 minutes
Excretionrenal
Identifiers
  • (2S,5R,6R)-6-(2,6-dimethoxybenzamido)-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid
JSmol)
  • OC(=O)[C@@H]2N3C(=O)[C@@H](NC(=O)c1c(OC)cccc1OC)[C@H]3SC2(C)C
 ☒NcheckY (what is this?)  (verify)

Methicillin (

β-lactam antibiotic of the penicillin
class.

Methicillin was discovered in 1960.[1]

Medical uses

Compared to other penicillins that face

susceptibility 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 the laboratory to determine the antibiotic sensitivity of Staphylococcus aureus to other penicillins facing β-lactam resistance; this role has now been passed on to other penicillins, namely cloxacillin, as well as genetic testing for the presence of mecA gene by PCR.[citation needed
]

Spectrum of activity

At one time, methicillin was used to treat infections caused by certain gram-positive bacteria including Staphylococcus aureus, Staphylococcus epidermidis, Streptococcus pyogenes, and Streptococcus pneumoniae. Methicillin is only effective against Staphylococcus aureus 50% of the time.

Resistance to methicillin is conferred by activation of a new bacterial

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. Expression of PBPA2 confers resistance to all β-lactams.[citation needed
]

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

Mechanism 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 (also known as penicillin-binding proteins (PBPs)). These PBPs crosslink glycopeptides (D-alanyl-alanine), forming the peptidoglycan cell wall. Methicillin 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).[3]

Methicillin is actually a

penicillinase
-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.

Medicinal chemistry

Methicillin is resistant to

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.[citation needed
]

History

Methicillin was developed by

penicillinase-producing organisms such as Staphylococcus aureus
that would otherwise be resistant to most penicillins.

Its role in therapy has been largely replaced by oxacillin (used for clinical antimicrobial susceptibility testing), flucloxacillin and dicloxacillin, but the term methicillin-resistant Staphylococcus aureus (MRSA) continues to be used to describe S. aureus strains resistant to all penicillins.[5]

References

  1. .
  2. ^ "Methicillin Sodium Susceptibility and Concentration (MIC) Data" (PDF). TOKU-E.
  3. ^ Gladwin M, Trattler B (2004). Clinical Microbiology made ridiculously simple (3rd ed.). Miami: MedMaster, Inc.
  4. . Retrieved 18 November 2010.
  5. .