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= Discovery and development of cephalosporins = Cephalosporins are a broad class of bacteriocidal antibiotics that include the β-lactam ring and share a structural similarity and mechanism of action with other β-lactam antibiotics (e.g. penicillins, carbapenems and aztrenoam). The cephalosporins (and other B-lactams) have the ability to kill bacteria by inhibiting essential steps in the bacterial cell wall synthesis which in the end results in osmotic lysis and death of the bacterial cell. Cephalosporins are widely used antibiotics because of their clinical efficiency and desirable safety profile.

The Cephalosporins diverse in their antibacterial spectrum, water solubility, acid tolerability, oral bioavailability, biological half time and other properties. Therefore the cephalosporins can ber further classified into generations depending on antibacterial activity, time of invention and structural basis.

History
The first chemical compounds of the cephalosporin group were isolated from Cephalosporium acremonium, a cephalosporin-producing fungus first discovered by Brotzu in 1948 from a sewage outfall off the Sardinian coast. From crude filtrates of the cephalosporium acremonium culture scientists got new antibacterial activity. It was noted that the crude filtrate could inhibit the growth of Staphylococcus aureus. Further investigations by Abraham and Newton were made in England and isolation of culture fluids from the sardinian fungus yielded cephalosporin P, N and C. These natural compounds were not found to be potent enough to use as antimicrobial agents but with chemical methods and removal of the natural side chain it was possible to produce 7-aminocephalosporanic acid (7-ACA) which could be further fitted with unnatural side chains. 7-ACA is analogous to 6-aminopenicillanic acid. (6-APA), a starting block for making several derivatives of penicillins. In 1959 when Abraham reported that his N-phenylacetyl derivative of Cephalosporin C was much more potent against Staphylococcus aureus strains than the parent compound. This derivative was later named Cephaloram, a cephalosporin analouge of benzylpenizillin. The 7-ACA production method at Oxford, acid hydrolysis of cephalosporin C had less than 1% yield of 7-ACA wich was way to low to be of commercial use. Another chemical method discovered in the laboratories of Eli Lilly had better yields of 7-ACA. That method was based on cleaving the alfa-aminoadipoyl sidechain of cephalosporin C. Further work by Robert Morin led to semisynthesis of 3-deacetoxy-7-ACA (7-ADCA) from penicillins which is convenient because penicillins can be fermented with more ease than cephalosporins. For example 7-ADCA can be semisynthesized in 7 chemical reaction steps from phenoxymethylpenicillin. Today we are left with thousands of semisynthetic analouges of natural cephalosporin compounds based on the knowlege gained by intensive research on the chemistry of those two starting materials.

Mechanism of action
The bacteriocidal effects of β-lactam antibiotics are achived through inhibition of the bacterian cell wall synthesis. The cell wall is a tight covalently bound and crosslinked peptidoglycan network and essential for bacterial growth, cell division and cellular structure. Therefore bacterias need enzymes that can cleave the cell wall during bacterial growth and cell seperation. The cell wall of bacterias is built up in two steps from the outside of the cell. In the first step, molecules of disaccaride units linked with peptides on their ends are transported from the cytoplasm of the bacteria  and joined together on the outside of the wall by a transglycolase enzyme. In the second step, a transpeptidase links together long polysaccaride chains wich are linked together through peptide bonds. The aminoacid sequence of D-alanyl-D-alanine is recognized by the transpeptidase at the end of the peptide chain, cleaves off the alanine on the terminal end and joins the remainder to a peptide chain from an adjacent polysaccaride. This transpeptidation reaction is inhibited by beta-lactam antibiotics like cephalosporins. Because of this inhibition the antibiotics are most effective when the bacteria´s are in the logarithmic phase of growth, were then they are synthesizing the cell wall. If the bacteria´s are in the stationary phase of growth then there is no wall synthesizing in progress and the antibiotics have much lower effect.

Although the mechanism of action for β-lactam antibiotics is not completely known they are believed to exert their Mechanism of action by mimicking the structure of the transition state of the chemical reaction when the transpeptidase is bound to the D-alanyl-D-alanine sequence. These proteins are often refered to as penicillin binding proteins. Opening of the β-lactam ring by a serine residue in the enzyme binding site or "pocket" leads to covalent binding of the antibiotic molecule with the active site of the enzyme. The result is an inactive irreversibly bound enzyme-complex which is incapable of further cell wall synthesis and the cell will die from osmotic lysis.