- Methicillin is a semi-synthetic β-lactam antibiotic that was developed in the late 1950s as part of the penicillin class of drugs. It was specifically designed to overcome bacterial resistance caused by the production of β-lactamase enzymes, which degrade natural penicillins like penicillin G and render them ineffective.
- Methicillin was created by modifying the penicillin molecule with a bulky side chain that protected the β-lactam ring from enzymatic breakdown, thereby restoring its ability to kill resistant Staphylococcus aureus strains. Upon its introduction in 1959, methicillin was considered a major advancement in the treatment of staphylococcal infections.
- The mechanism of action of methicillin, like other β-lactam antibiotics, involves inhibition of penicillin-binding proteins (PBPs)—enzymes critical for bacterial cell wall synthesis. By binding irreversibly to these PBPs, methicillin prevents the cross-linking of peptidoglycan chains, weakening the bacterial cell wall and ultimately leading to cell lysis and death. Its greatest strength lay in its stability against staphylococcal β-lactamases, which had compromised earlier penicillins. This made methicillin an important therapeutic option for serious infections such as bloodstream infections, pneumonia, and osteomyelitis caused by resistant S. aureus.
- However, methicillin use was relatively short-lived. It required intravenous administration, had limited stability, and carried a risk of adverse effects, particularly interstitial nephritis, which restricted its widespread clinical use. Within just a few years of its introduction, resistant strains of Staphylococcus aureus—known as methicillin-resistant Staphylococcus aureus (MRSA)—began to emerge. MRSA was first reported in 1961 in the United Kingdom, marking the beginning of a global public health challenge that continues today. These strains acquired the mecA gene, which encodes a modified PBP (PBP2a) with low affinity for methicillin and other β-lactams, making the entire drug class ineffective against them.
- Although methicillin itself is no longer widely used in clinical practice, its legacy is highly significant. It gave rise to the broader class of penicillinase-resistant penicillins, such as oxacillin, cloxacillin, dicloxacillin, and flucloxacillin, which remain in use today against non-MRSA staphylococcal infections. Importantly, the term “methicillin-resistant” persists in medicine as a historical reference to MRSA, even though oxacillin and cefoxitin are now used in laboratory testing as more reliable indicators of resistance.
