Discovery and development of cephalosporins

[3] The cephalosporins are diverse in their antibacterial spectrum, water solubility, acid tolerability, oral bioavailability, biological half-life and other properties.

[4][5] The first chemical compounds of the cephalosporin group were isolated from Cephalosporium acremonium, a cephalosporin-producing fungus first discovered by Giuseppe Brotzu in 1948 from a sewage outfall off the Sardinian coast.

[3] Further investigations by Sir Edward Abraham and Guy 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 fit with unnatural side chains.

[1] In 1959 Abraham reported that his N-phenylacetyl derivative of cephalosporin C was much more potent against Staphylococcus aureus strains than the parent compound.

The clinical successes of these two cephalosporins urged researchers to improve the pharmacological properties and develop more agents.

[8][9] Today we are left with thousands of semisynthesized analogues of natural cephalosporin compounds based on the knowledge gained by intensive research on the chemistry of those two starting materials.

[1] The bactericidal effects of β-lactam antibiotics are achieved through inhibition of the bacterial cell wall synthesis.

In the first step, molecules of disaccharide 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.

The enzyme cleaves off the alanine on the terminal end and joins the remainder to a peptide chain from an adjacent polysaccharide.

Because of this inhibition the antibiotics are most effective when the bacteria are in the logarithmic phase of growth, where then they are synthesizing the cell wall.

If the bacteria are in the stationary phase of growth, then there is no wall synthesizing in progress, and the antibiotics have much lower effect.

[2][10][11] The molecular structure of cephalosporin can be altered in various ways to improve in vitro stability, anti-bacterial activity and resistance against β-lactamases.

In the acidic conditions of the stomach, in vitro stability can be enhanced by the addition of an amino and a hydrogen to positions α1 and α2 of the cephalosporin structure.

This results in a basic compound, an ammonium ion that is protonated in said conditions, giving us a more stable β-lactam which leads to an orally active drug.

[12] Most bacterial species have various types of PBP which differ in various ways such as enzymatic function, molecular weight and the affinity for β-lactam antibiotics.

Target alterations in the binding site of PBP have led to high-level resistance of β-lactams among bacteria like staphylococci, enterococci and pneumococci.

[13] For example, the binding site of PBP2 in Neisseria gonorrhoeae has been structurally determined and has three sequence motifs that can be seen in nearly all β-lactam interacting enzymes: Research also implies that adjacent regions to the active site which differ between different PBP have significant influence on the rate of β-lactam acylation rate.

[citation needed] Cephalosporins must get through the bacterial cell wall in order to reach the target PBP.

The cell wall structure of gram-positive bacteria is made routinely up by peptidoglycan which allows the passage of cephalosporin-sized molecules.

The cell wall structure of gram-negative bacteria is more complex, composed of polysaccharides, lipids and proteins, and is harder to penetrate.

[16] Bacteria species such as pneumococci and meningococci can acquire exogenous genetic material, and incorporate it into their own chromosomes which leads to antimicrobial resistance.

Gram-positive bacteria, such as a staphylococci, have a high release of beta-lactamases into their extracellular space, where they meet the drug outside the cell wall.

The generation classification system relies on dividing the cephalosporins by their chemical properties and their relative activity against gram-negative versus gram-positive bacteria.

This chemical property gives loracarbef better stability in plasma while retaining oral absorption characteristics and affinity for binding to PBP.

An important structural change in the development of second generation cephalosporins was the introduction of an α-iminomethoxy group to the C-7 side chain.

Many of the oral third generation cephalosporins are esters of parenteral forms and are hydrolysed by esterases in the digestive tract (cefteram pivoxil).

Ceftobiprole also has an aminothiazoyl-hydroxyimino side chain at the C-7 position which is known to give good resistance to β-lactamase from S. aureus.