penicillin

penicillin
Name	penicillin
Width	200
Caption	Core structure of penicillins, featuring the β-lactam ring.
Pronounce	/ˌpɛnɪˈsɪlɪn/
Tradename	Various
Drugs.com	monograph, penicillin-v-potassium
Legal AU	S4
Legal UK	POM
Legal US	℞-only
Routes of administration	Oral, intravenous, intramuscular
CAS number	61-33-6
ATC prefix	J01
ATC suffix	CA

penicillin. It is a group of antibiotics derived from Penicillium fungi, historically the first medication effective against many bacterial infections caused by staphylococci and streptococci. Its discovery and development revolutionized medicine, marking the dawn of the antibiotic era and saving countless lives from previously fatal diseases. The term often refers to benzylpenicillin (penicillin G), but encompasses a broad range of β-lactam antibiotics.

History

The antibacterial properties of Penicillium mould were first observed in 1928 by Alexander Fleming at St Mary's Hospital, London. Fleming noted that a Staphylococcus culture plate contaminated by the mould showed a clear zone where bacterial growth was inhibited. He named the substance "penicillin" but could not purify it for therapeutic use. A decade later, a team at the University of Oxford led by Howard Florey and including Ernst Chain and Norman Heatley successfully isolated and produced the drug. Their work, accelerated by World War II, led to the first successful clinical trials and mass production, aided by research in the United States at the Northern Regional Research Laboratory. Fleming, Florey, and Chain shared the 1945 Nobel Prize in Physiology or Medicine for this achievement. Large-scale manufacturing was pioneered by companies like Pfizer and Merck & Co., playing a crucial role in treating infected wounds among Allied forces.

Medical uses

It is primarily used to treat infections caused by susceptible Gram-positive bacteria. It remains a first-line treatment for conditions like streptococcal pharyngitis (strep throat), syphilis caused by Treponema pallidum, and meningitis caused by Streptococcus pneumoniae. It is also effective against certain Gram-negative bacteria such as Neisseria meningitidis. In hospital settings, it is used for serious infections including endocarditis and clostridial infections like gas gangrene. Prophylactic use is common to prevent rheumatic fever and in procedures with a risk of bacterial endocarditis, as recommended by the American Heart Association.

Mechanism of action

It exerts its bactericidal effect by inhibiting the synthesis of the bacterial cell wall. It binds to and inactivates enzymes known as penicillin-binding proteins (PBPs), which are essential for catalyzing the final step of peptidoglycan cross-linking in the cell wall. This action primarily occurs during the final stage of bacterial cell wall assembly. The inhibition weakens the peptidoglycan layer, especially in actively dividing cells, leading to osmotic lysis and cell death due to the high internal osmotic pressure of the bacterium. Its effectiveness is greatest against growing and dividing organisms.

Structure and variants

All penicillins share a core structure consisting of a thiazolidine ring fused to a β-lactam ring, which is essential for antibacterial activity; this combined ring system is called the penam skeleton. The natural product, benzylpenicillin (penicillin G), has a benzyl side chain. Modifications to this side chain have produced numerous semi-synthetic variants with improved properties. These include phenoxymethylpenicillin (penicillin V), which is acid-stable for oral administration; methicillin and oxacillin, which are resistant to beta-lactamase; and ampicillin and amoxicillin, which have broader spectra of activity against Gram-negative bacteria.

Production

Initial commercial production utilized deep-tank fermentation of the mould Penicillium chrysogenum in large bioreactors, a method developed during World War II. The process involves growing the fungus in a nutrient-rich broth, often containing corn steep liquor. The antibiotic is a secondary metabolite, produced only after the initial growth phase. After fermentation, it is extracted and purified through a series of steps including solvent extraction and crystallization. Most modern production still relies on high-yielding strains of Penicillium chrysogenum derived from the original isolate found on a Cantaloupe in Peoria, Illinois.

Resistance

Bacterial antibiotic resistance to it is a major global health concern. The primary mechanism is the production of beta-lactamase enzymes (such as penicillinase) by bacteria like Staphylococcus aureus, which hydrolyze the β-lactam ring, inactivating the drug. Resistance can also occur through alterations in penicillin-binding proteins (PBPs) that reduce the drug's affinity, as seen in methicillin-resistant Staphylococcus aureus (MRSA). Additionally, some Gram-negative bacteria possess outer membranes that limit drug penetration. The widespread use and misuse of antibiotics in medicine and agriculture have accelerated the spread of resistant strains, complicating treatment.

Side effects and interactions

Adverse effects are generally uncommon but can be serious. The most frequent is a hypersensitivity reaction, ranging from a mild skin rash to life-threatening anaphylaxis. Cross-reactivity can occur with other β-lactam antibiotics like cephalosporins. High doses, particularly of penicillin G, may cause neurotoxicity including seizures. It can alter gut flora, potentially leading to diarrhea or secondary infections like Clostridioides difficile. Significant drug interactions include reduced effectiveness with bacteriostatic antibiotics and potential interference with the action of aminoglycosides when mixed in vitro. Probenecid is sometimes administered concurrently to delay renal excretion and increase serum concentrations.

Category:Antibiotics Category:World Health Organization essential medicines Category:Discoveries by Alexander Fleming