Beta lactam antibiotics
Introduction
β-Lactam antibiotics are the most commonly used class of antibiotics and the first class of these drugs discovered. Alexander Fleming isolated the first β-lactam antibiotic, penicillin, in 1929 from a strain of Penicillium rubens [fig 1]. His accidental discovery of the drug revolutionized the treatment of bacterial infections; this class is now the most commonly prescribed injectable antibiotic in the US (1). This family of drugs is named for their central 4-membered cyclic amide (called a lactam) [fig 2]. Many investigations have converged upon the thesis that this ring, due to susceptibility for nucleophilic attack, irreversibly binds a serine residue on penicillin binding proteins, preventing complete synthesis of the bacterial cell wall. (2) Due to the widespread use of this class of drugs, bacteria have evolved to resist them by producing the enzyme β-lactamase.
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Historical Overview
In September 1928, Alexander Fleming returned to his laboratory after a vacation to find mold growing alongside bacteria in some petri dishes he had left out. A clear ring had formed around the blue-green mold where no bacteria was growing (3). Fleming was interested in this result because several years prior, he discovered that his nasal mucus inhibited bacterial growth on a plate. This result was later found to be caused by an enzyme, rather than a small molecule, which Fleming named lysozyme (4). Nevertheless, this discovery made Fleming perceptive enough to notice the effects of the mold on bacterial growth.
In 1929, Fleming reported his findings in the British Journal of Experimental Pathology. In the article, Fleming made some attempts to characterize the antibacterial agent such as documenting the effects of boiling and filtering its concentrated solutions. He found that neither of these processes affected the antibacterial nature of the solution (5). He tested varying dilutions of the stock solution and found that even when the mold juice was diluted 800 times, the growth of a staphylococcus species was still inhibited. Fleming used rabbits to test the toxicity of the concentrated solutions and found it to be well tolerated, suggesting that the drug could be useful for combating bacterial infections in humans.
In 1940, clinical experiments began at Oxford University to formulate penicillin as a drug for human medicine (6). While Flemming initially thought penicillin was only effective as a topical anesthetic, the Oxford studies quickly found that it could also be injected safely or taken as an oral medication. The English biochemist Edward Abraham was the first to propose a chemical structure of penicillin, but Dorothy Hodgkin was able to determine its precise structure using x-ray crystallography. In 1941 Howard Florey and Norman Heatley of the Oxford research group travelled to the US to persuade the USDA to begin manufacturing penicillin at a large scale. Production started and the drug became available to the public by 1945. Current production methods are essentially the same as the first industrial processes of the 1940s–the fungus Penicillium rubens is grown in large tanks of liquid culture containing sugars and the penicillin produced by biosynthesis is then purified.
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References
- ↑ 1.0 1.1 1.2 Zigli DD, Brew L, Obeng-Denteh W, Kwofie S. On the Application of Homeomorphism on Amoeba Proteus. Ghana Journal of Technology. 2021 Mar 31;5(2):43-7.
- ↑ Bartlett et al.: Oncolytic viruses as therapeutic cancer vaccines. Molecular Cancer 2013 12:103.
- ↑ Lee G, Low RI, Amsterdam EA, Demaria AN, Huber PW, Mason DT. Hemodynamic effects of morphine and nalbuphine in acute myocardial infarction. Clinical Pharmacology & Therapeutics. 1981 May;29(5):576-81.
- ↑ 4.0 4.1 text of the citation
- ↑ 5.0 5.1 Murphy A, Barich D, Fennessy MS, Slonczewski JL. An Ohio State Scenic River Shows Elevated Antibiotic Resistance Genes, Including Acinetobacter Tetracycline and Macrolide Resistance, Downstream of Wastewater Treatment Plant Effluent. Microbiology Spectrum. 2021 Sep 1;9(2):e00941-21.
Edited by [Author Name], student of Joan Slonczewski for BIOL 116, 2024, Kenyon College.
