Penicillin G

Penicillin G
IUPAC name	(2S,5R,6R)-3,3-Dimethyl-7-oxo-6-[(2-phenylacetyl)amino]-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid
Tradename	Bicillin, Pfizerpen, others
CAS number	61-33-6
DrugBank	DB01053
UNII	Q42T66VG0C
ChEMBL	CHEMBL29
Synonyms	Benzylpenicillin

Penicillin G. It is a narrow-spectrum beta-lactam antibiotic of the penicillin class and was the first widely used antibiotic agent. Discovered from the fungus Penicillium rubens, it remains a critical treatment for many serious bacterial infections, particularly those caused by susceptible Gram-positive bacteria. Its clinical utility is primarily against infections involving Streptococcus pyogenes, certain strains of Staphylococcus aureus, and the spirochete Treponema pallidum.

History

The antibacterial properties of the Penicillium mold were first observed by Ernest Duchesne in 1896 and later famously rediscovered by Alexander Fleming at St. Mary's Hospital, London in 1928. The isolation and purification of the active compound was achieved by a team led by Howard Florey and Ernst Chain at the University of Oxford, a effort massively scaled up during World War II with support from the United States Department of Agriculture and pharmaceutical firms like Pfizer. Its first widespread medical use followed the successful treatment of Anne Miller in 1942, and the developers were jointly awarded the Nobel Prize in Physiology or Medicine in 1945. Large-scale production was pioneered using deep-tank fermentation techniques developed by Margaret Hutchinson Rousseau.

Medical uses

It is a first-line agent for infections caused by susceptible organisms, including syphilis caused by Treponema pallidum, serious Streptococcus pneumoniae infections like meningitis, and infections from Streptococcus pyogenes such as necrotizing fasciitis. It is also used for prophylaxis against rheumatic fever and in the management of actinomycosis, clostridial infections like gas gangrene, and Leptospira interrogans infections. It is often administered intravenously in hospital settings for severe conditions like endocarditis and osteomyelitis.

Mechanism of action

As a beta-lactam antibiotic, it inhibits bacterial cell wall synthesis by irreversibly binding to penicillin-binding proteins located on the inner membrane of the bacterial cell wall. This binding activity disrupts the final transpeptidation step in the synthesis of peptidoglycan, a critical component of the cell wall. The resulting inhibition prevents the formation of cross-links within the peptidoglycan layer, leading to cell lysis and death, particularly in actively dividing bacteria. Its structure mimics the D-alanyl-D-alanine terminus of the peptidoglycan precursor, allowing it to act as a substrate analog.

Pharmacokinetics

It is poorly absorbed from the gastrointestinal tract and is therefore typically administered via intravenous or intramuscular injection. It distributes widely throughout the body, achieving good concentrations in tissues and fluids including pleural fluid, synovial fluid, and peritoneal fluid, though penetration into the cerebrospinal fluid is poor unless the meninges are inflamed. It is primarily excreted unchanged by the renal tubules, with a significant portion also cleared via active secretion; its half-life is short, approximately 30 to 60 minutes in adults with normal renal function.

Adverse effects

The most common adverse effect is a hypersensitivity reaction, which can range from a mild maculopapular rash to life-threatening anaphylaxis. Other notable adverse reactions include Jarisch-Herxheimer reaction during treatment for syphilis, neurotoxicity at very high doses manifesting as myoclonus or seizures, and electrolyte imbalance when administered as the potassium or sodium salt. Interstitial nephritis and hemolytic anemia are rare but serious complications. Cross-reactivity with other beta-lactam antibiotics like cephalosporins can occur.

Production

Commercial production is achieved through a large-scale fermentation process using high-yielding strains of the filamentous fungus Penicillium chrysogenum. The process occurs in specialized bioreactors under controlled conditions of temperature, pH, and aeration, utilizing a growth medium containing corn steep liquor, lactose, and mineral salts. After fermentation, the antibiotic is extracted using organic solvents like butyl acetate or methyl isobutyl ketone and then purified through crystallization, often recovered as the stable potassium salt or procaine penicillin G salt for various formulations.

Category:World Health Organization essential medicines Category:Penicillin antibiotics Category:Discoveries by Alexander Fleming