Methicillin ( USAN), also known as meticillin ( INN), is a narrow-spectrum β-lactam antibiotic of the

penicillin Penicillins (P, PCN or PEN) are a group of β-lactam antibiotics originally obtained from '' Penicillium'' moulds, principally '' P. chrysogenum'' and '' P. rubens''. Most penicillins in clinical use are synthesised by P. chrysogenum usin ...

class. Methicillin was discovered in 1960.

Medical uses

Compared to other penicillins that face antimicrobial resistance due to β-lactamase, it is less active, can be administered only

parenterally A route of administration in pharmacology and toxicology is the way by which a drug, fluid, poison, or other substance is taken into the body. Routes of administration are generally classified by the location at which the substance is applied. ...

, and has a higher frequency of

interstitial nephritis Interstitial nephritis, also known as tubulointerstitial nephritis, is inflammation of the area of the kidney known as the renal interstitium, which consists of a collection of cells, extracellular matrix, and fluid surrounding the renal tubul ...

, an otherwise-rare

adverse effect An adverse effect is an undesired harmful effect resulting from a medication or other intervention, such as surgery. An adverse effect may be termed a " side effect", when judged to be secondary to a main or therapeutic effect. The term compl ...

of penicillins. However, selection of methicillin depended on the outcome of 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 A laboratory (; ; colloquially lab) is a facility that provides controlled conditions in which scientific or technological research, experiments, and measurement may be performed. Laboratory services are provided in a variety of settings: physi ...

to determine the antibiotic sensitivity of ''

Staphylococcus aureus ''Staphylococcus aureus'' is a Gram-positive spherically shaped bacterium, a member of the Bacillota, and is a usual member of the microbiota of the body, frequently found in the upper respiratory tract and on the skin. It is often posit ...

'' 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 ''mecA'' is a gene found in bacterial cells which allows them to be resistant to antibiotics such as methicillin, penicillin and other penicillin-like antibiotics. The bacteria strain most commonly known to carry ''mecA'' is methicillin-resista ...

'' gene by '' PCR''.

Spectrum of activity

At one time, methicillin was used to treat infections caused by certain

gram-positive bacteria In bacteriology, gram-positive bacteria are bacteria that give a positive result in the Gram stain test, which is traditionally used to quickly classify bacteria into two broad categories according to their type of cell wall. Gram-positive bac ...

including ''Staphylococcus aureus'', ''Staphylococcus epidermidis'', ''Streptococcus pyogenes'', and ''Streptococcus pneumoniae''. Methicillin is no longer effective against these organisms due to resistance. Resistance to methicillin is conferred by activation of a new bacterial penicillin binding protein (PBP) '' 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. These susceptibility data are given on a few medically significant bacteria: * ''Staphylococcus aureus'' - 0.125 - >100 μg/ml * Methicillin resistant Staphylococcus aureus (MRSA) - 15.6 - >1000 μg/ml * ''Streptococcus pneumoniae'' 0.39 μg/ml

Mechanism of action

Like other beta-lactam antibiotics, methicillin acts by inhibiting the synthesis of bacterial

cell wall A cell wall is a structural layer surrounding some types of cells, just outside the cell membrane. It can be tough, flexible, and sometimes rigid. It provides the cell with both structural support and protection, and also acts as a filtering mec ...

s. 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). 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 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 Steric effects arise from the spatial arrangement of atoms. When atoms come close together there is a rise in the energy of the molecule. Steric effects are nonbonding interactions that influence the shape ( conformation) and reactivity of ions ...

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

History

Methicillin was developed by Beecham in 1959. It was previously used to treat

infection An infection is the invasion of tissues by pathogens, their multiplication, and the reaction of host tissues to the infectious agent and the toxins they produce. An infectious disease, also known as a transmissible disease or communicable di ...

s caused by susceptible gram-positive bacteria, in particular, penicillinase-producing organisms such as ''

'' 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 Methicillin-resistant ''Staphylococcus aureus'' (MRSA) is a group of Gram-positive bacteria that are genetically distinct from other strains of '' Staphylococcus aureus''. MRSA is responsible for several difficult-to-treat infections in human ...

(MRSA) continues to be used to describe ''S. aureus'' strains resistant to all penicillins.

References

{{Cell wall disruptive antibiotics Penicillins Benzamides Phenol ethers