Methicillin (

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), also known as meticillin (

INN Inns are generally establishments or buildings where travelers can seek lodging, and usually, food and drink. Inns are typically located in the country or along a highway; before the advent of motorized transportation they also provided accommo ...

), is a narrow-spectrum

β-lactam antibiotic β-lactam antibiotics (beta-lactam antibiotics) are antibiotics that contain a beta-lactam ring in their chemical structure. This includes penicillin derivatives (penams), cephalosporins and cephamycins (cephems), monobactams, carbapenems and ...

of the penicillin class. Methicillin was discovered in 1960.

Medical uses

Compared to other penicillins that face

antimicrobial resistance Antimicrobial resistance (AMR) occurs when microbes evolve mechanisms that protect them from the effects of antimicrobials. All classes of microbes can evolve resistance. Fungi evolve antifungal resistance. Viruses evolve antiviral resistance. P ...

due to

β-lactamase Beta-lactamases, (β-lactamases) are enzymes () produced by bacteria that provide multi-resistance to beta-lactam antibiotics such as penicillins, cephalosporins, cephamycins, monobactams and carbapenems ( ertapenem), although carbapenems ...

, it is less active, can be administered only parenterally, 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 tubules ...

, 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: physic ...

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 Cloxacillin is an antibiotic useful for the treatment of a number of bacterial infections. This includes impetigo, cellulitis, pneumonia, septic arthritis, and otitis externa. It is not effective for methicillin-resistant ''Staphylococcus aureus ...

'', as well as genetic testing for the presence of '' mecA'' gene by '' PCR''.

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 no longer effective against these organisms due to resistance. Resistance to methicillin is conferred by activation of a new bacterial

penicillin binding protein Penicillin-binding proteins (PBPs) are a group of proteins that are characterized by their affinity for and binding of penicillin. They are a normal constituent of many bacteria; the name just reflects the way by which the protein was discove ...

(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 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 humans. ...

(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 walls. It inhibits cross-linkage between the linear

peptidoglycan Peptidoglycan or murein is a unique large macromolecule, a polysaccharide, consisting of sugars and amino acids that forms a mesh-like peptidoglycan layer outside the plasma membrane, the rigid cell wall (murein sacculus) characteristic of most ba ...

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 Penicillin-binding proteins (PBPs) are a group of proteins that are characterized by their affinity for and binding of penicillin. They are a normal constituent of many bacteria; the name just reflects the way by which the protein was discove ...

(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

(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 Beta-lactamases, (β-lactamases) are enzymes () produced by bacteria that provide multi-resistance to beta-lactam antibiotics such as penicillins, cephalosporins, cephamycins, monobactams and carbapenems ( ertapenem), although carbap ...

(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

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 dis ...

s 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

oxacillin Oxacillin (trade name Bactocill) is a narrow-spectrum beta-lactam antibiotic of the penicillin class developed by Beecham. It was patented in 1960 and approved for medical use in 1962. Medical uses Oxacillin is a penicillinase-resistant β ...

(used for clinical antimicrobial susceptibility testing),

flucloxacillin Flucloxacillin, also known as floxacillin, is an antibiotic used to treat skin infections, external ear infections, infections of leg ulcers, diabetic foot infections, and infection of bone. It may be used together with other medications to t ...

and

dicloxacillin Dicloxacillin is a narrow-spectrum β-lactam antibiotic of the penicillin class. It is used to treat infections caused by susceptible (non-resistant) Gram-positive bacteria.Product Information: DICLOXACILLIN SODIUM-dicloxacillin sodium capsule. T ...

, 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