Discovery and development of cephalosporins
The cephalosporins are diverse in their antibacterial
Basic structure of cephalosporins
The core of the basic cephalosporin molecule consists of a two ring system which includes a β-lactam ring condensed with dihydrothiazine ring. The core itself can also be referred to as 7-aminocephalosporanic acid which can be derived by hydrolysis from the natural compound cephalosporin C. Chemical compounds containing this core are relatively stable to acid hydrolysis and tolerance to β-lactamases. Cephalosporin C contains a side-chain which is derived from D-aminoadipic acid. Modification of side chains on the relevant positions has been used to create a whole new class of cephalosporin antibiotics. Modification of side-chains in position 7 of the lactam ring seems to affect the antibacterial activity while position 3 of the dihydrothiazine ring alters pharmacokinetic properties and receptor binding affinity.[4][5]
Discovery
The first chemical compounds of the cephalosporin group were isolated from
Investigation
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. 7-ACA is analogous to 6-aminopenicillanic acid (6-APA), a starting block for making several derivatives of penicillins.[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. This derivative was later named Cephaloram, a cephalosporin analogue of benzylpenicillin.[citation needed]
Eli Lilly developed a method for producing 7-ACA based on cleaving the α-aminoadipoyl side chain of cephalosporin C.[6] 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 seven chemical reaction steps from phenoxymethylpenicillin.[1]
Results
Mechanism of action
The bactericidal effects of β-lactam antibiotics are achieved through inhibition of the bacterial cell wall synthesis. The
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.
Drug design
Structure activity relationship
The molecular structure of cephalosporin can be altered in various ways to improve
Binding site
Advances in the field of
Most bacterial species have various types of PBP which differ in various ways such as enzymatic function,
- SXXK motif is located at the N-terminal end of α2 helix and includes two residues that are important for the enzyme function.
- Ser-310 : Includes a substrateand β-lactam antibiotics.
- Lys-313 : Plays an important role in providing the dense hydrogen bound network at the active site and is in distance of Ser 310, ASN-364 and the carbonylbackbone of Ser-362.
- Ser-310 : Includes a
- SXN motif that includes Ser-362, Ser-363 and Asn-364
- KTG motif that includes Lys-497, Thr-498 and Gly-499
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.[14]
Antimicrobial resistance
- Modifications in target PBP
- Drug inactivation by bacterial β-lactamases
- Drug not being able to reach target PBP in the bacterial cell
Cephalosporins must get through the bacterial cell wall in order to reach the target PBP. In comparison, it is easier to penetrate the cell wall of gram-positive bacteria than the cell wall of gram-negative bacteria. 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. Particles get through the outer membrane through water-filled channels, or porins, which are trans membrane proteins.[15] During exposure to cephalosporins the bacteria can form resistance by itself or as selection of the next generation of bacteria after reproducing itself, by mutation.[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.[17] In that manner the target PBP can be altered to have their attraction for cephalosporins and other β-lactam antibiotics lowered.[18][19] The bacteria can also replace the PBP that is vulnerable to Beta-lactam antibiotics with PBP that is less vulnerable.[20] β-lactam antibiotics can be inactivated by many types of
Drug development
This section will review the drug development from one generation to the next with emphasis on the structural differences between the generations. The generation classification system relies on dividing the cephalosporins by their chemical properties and their relative activity against gram-negative versus gram-positive bacteria.[5][14] From the first generation cephalosporins to the third generation there is a development from being more effective against gram-positive bacteria to being more effective against gram-negative bacteria and less effective against gram-positive bacteria respectively. However the activity returns to a balanced effectiveness against gram-negative and gram-positive bacteria in the fourth generation.[23]
Classification of cephalosporins
The cephalosporin class is very extensive so a good classification system is necessary to distinguish different cephalosporins from each other. There are few chemical and activity features that could be used for classification, for example chemical structure, side chain properties, pharmacokinetic, spectrum of activity or clinical properties. Despite these variable features the most common classification system for cephalosporins is to divide them into generations. The generation system is based on different antimicrobial activity shown by different cephalosporins.[3][4][24]
1st generation cephalosporins
First generation cephalosporins were the first cephalosporins on the market. They have good antimicrobial activity against gram-positive bacteria but limited activity against gram-negative species.[25] The chemical structures of the first generation cephalosporins are fairly simple. As an example three drugs from this class (cefalexin, cefradine and cefadroxil) all have a single methyl group at position C-3. The common side groups at C-3 for first class cephalosporins are small uncharged groups like methyl.[5] The methyl group at position C-3 gives low affinity for common PBP which can in part explain the relatively low activity of these first drugs. Cefaclor however has a Cl group at position C-3 which gives it better binding to PBP and thus better antimicrobial activity. There is not an agreement on classifying cefaclor as a first generation cephalosporin because of the Cl group at the C-3 position and therefore its improved activity, but it is often classified as such because of its C-7 side chain which is more related to the first generation than the second. All of the first generation cephalosporins have an α-amino group at position C-7. This structure makes them vulnerable to hydrolysis by β-lactamases.[5][9]
2nd generation cephalosporins
3rd generation cephalosporins
4th generation cephalosporins
The fourth generation cephalosporins have greater activity against gram-negative bacteria than the second and third generation. This difference is attributed to them being dipolar ionic zwitterion compounds. The C-7 side chain is similar to third generation cephalosporins usually containing iminomethoxy-aminothiazole group or in the case of cefclidin an aminothiadiazole. Because of the positively charged quaternary nitrogen in the C-3 side chain fourth generation cephalosporins can diffuse through the gram-negative bacterial membrane more readily than earlier cephalosporins. It is thought that the positive charge orients the drug molecule to the entrance of the porin channel.[26]
5th generation cephalosporins
Currently there are only two drugs in this category,
Current status
Antimicrobial resistance is the driving force for the development of new antimicrobial agents. The complexity and diversity of resistance mechanisms has defined the need for new and improved β-lactam antibiotics.[29] With their broad spectrum the cephalosporins have come to dominate β-lactam chemotherapy although they often lack oral bioavailability.[9]
On 29 October 2010, a new cephalosporin agent - Ceftarolin - was approved by the
Ceftobiprole has been approved for the treatment of adult patients with hospital acquired pneumonia (excluding VAP) and community acquired pneumonia in 12 European countries, Canada and Switzerland.[30][31]
See also
- Discovery and development of mTOR inhibitors
References
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