Penicillins molecular structure

P-Lactamases are enzymes that hydrolyze the P-lactam ring of P-lactamantibiotics (penicillins, cephalosporins, monobactams and carbapenems). They are the most common cause of P-lactam resistance. Most enzymes use a serine residue in the active site that attacks the P-lactam-amid carbonyl group. The covalently formed acylester is then hydrolyzed to reactivate the P-lacta-mase and liberates the inactivated antibiotic. Metallo P-lactamases use Zn(II) bound water for hydrolysis of the P-lactam bond. P-Lactamases constitute a heterogeneous group of enzymes with differences in molecular structures, in substrate preferences and in the genetic localizations of the encoding gene (Table 1). 

Woodward then moved across town in Cambridge to devote a year of postgraduate study at Harvard University. At the end of that year, he accepted an appointment to the Harvard chemistry faculty, a post he held for most of the rest of his life. One of his great interests at Harvard was the synthesis of large, complex molecules, the first of which was quinine in 1944. He followed that work with the elucidation of other molecular structures and the development of synthetic methods for each. Included among these molecules were penicillin (1945), patulin (1948), cholesterol and cortisone (1951), oxytetracycline (1952), strychnine (1954), lysergic acid (1954), reserpine (1956), chlorophyll (1960), colchicine (1963), cephalosporin C (1965), and vitamin (1971). 

The most powerful technique for determining the structure of a chemical compound is x-ray crystallography. In this technique, a beam of x rays is focused on a crystal of a compound. The diffraction pattern produced enables chemists to determine the location of atoms within the crystals and hence deduce the molecular structure. It was Dorothy Hodgkin who pushed the limits of the technique to determine the structures of some biologically important molecules, including penicillin, vitamin B12, and insulin. 

In 1942, Crowfoot embarked upon the molecular structure of penicillin. Structural studies were essential to help in the synthesis of penicillin, a task which was of vital importance during the war. Fortunately, she had met biochemist Ernst Chain62 some years earlier in the streets of Oxford, and he had promised... 

As with the penicillins, hypersensitivity reactions are the most common systemic adverse events caused by cephalosporins. Maculopapular rash, urticaria, fever, bron-chospasm,and anaphylaxis have been associated with the use of cephalosporins.Because the molecular structure of the penicillins and the first-generation cephalosporins are similar, there is a risk in patients who are aUergic to penicillin to manifest aUergic cross-reactions when prescribed any of this gronp of cephalosporins. In contrast, the risk of cross-reactivity between the penicUUns and the second-, third-, and fonrth-generation cephalosporins has been overestimated, and patients with a previons aUergic... 

Cephalosporins were first obtained from a filamentous fungus Cephalosporium cultured from the sea near a Sardinian sewage outfall in 1945 their molecular structure is closely related to that of penicillin, and many semisynthetic forms have been introduced. They now comprise a group of antibiotics having a wide range of activity and low toxicity. The term cephalosporins will be used here in a general sense although some are strictly cephamycins, e.g. cefoxitin and cefotetan. 

Copper(II) binds some 10-fold more strongly to cephalosporins than to penicillins. " Molecular models indicate that one of the conformations of cephalosporins would be very suitable for binding via the carboxylate group and the /8-lactam carbonyl oxygen (124) giving rise to a seven-membered chelate ring. Variations in the /3-lactam carbonyl stretching frequency on com-plexation provide some support for structure (124). 

FIGURE 7.33 Molecular structures of some antibiotics (a) sulfanilamide (b) penicillin G and (c) tetracycline. 

In 1933 after a brief stint at Cambridge and Oxford, she returned to Somerville and Oxford in 1934 and remained there for most of her life teaching chemistry. In 1934 she crystallized and X-ray photographed insulin, only the second protein to be studied. She went on to map the molecular structure of penicillin (1947) and vitamin B12 (1956). In the late 1960s, she created a three-dimensional map of insulin. 

Many important therapeutics, in use in clinics today, are biosynthesized by the nonribosomal peptide synthetase (NRPS) and polyketide synthase (PKS) paradigm. For example, many of the antibiotics (penicillin, cephalosporin, vancomycin, erythromycin, etc.), immunosuppressors (cyclosporine, rapamycin), antiviral agents (luzopeptin A), antitumor agents (bleomycin), and toxins (thaxtomin) are NRPS and PKS derived.20-22 Figure 1 displays a small selection of natural products that are NRPS and PKS derived and illustrates the diversity of molecular structures generated by these biosynthetic paradigms. 

Little is known as yet about the molecular mechanisms by means of which chlortetracycline is able to control some viral diseases and penicillin (the formula of penicillin K is CuHisO S) is able to control many bacterial diseases. Knowledge of the molecular structure of chlortetracycline and penicillin does not by itself give the solution of the great problem of the molecular basis of the action of drugs and the nature of disease. We need also to know the molecular structure of the human body, of bacteria, of viruses. When these problems have been solved it will be possible to apply much of our present knowledge, as well as the new knowledge, in a way that will benefit all humanity. 

This is just in contrast to another approach of modifying the molecular structure of peptidic compounds on the biosynthetic level, namely the directed biosynthesis of the desired compound structures by feeding of appropriate biosynthetic precursors or stimulating agents during fermentation, as it is routinely performed for production of penicillin V und G by the addition of phenoxyacetic acid or phenyl-acetic acid, respectively, as precursors to facilitate penicillin extraction from the culture broth. 

FIGURE 5.37 Chemical structure of a molecular probe with UV-Vis and fluorescence outputs for penicillin G amidase activity. The phenylacetamide group (red) is a substrate for PGA. The reporter units, 4-nitrophenol and 6-aminoquinoline, provide a visible signal and a fluorescence signal, respectively, upon release. (See the color version of this figure in Color Plates section.)... 

An interesting example of MIP-LC analytics was presented in a paper, which focused on the separation of antibiotics of similar structures. Columns are (commercially) available to separate penicillins ( 3-lactams) from other antibiotics. However, if the quantification of each of the 3-lactam compounds is required, a more selective stationary phase has to be found. Molecular imprinting allows the fabrication of phases specifically for each 3-lactam. If for instance the concentration of the P-lactam oxacillin in a food sample has to be selectively determined, a polymer imprinted with oxacillin is the right choice. Compared to a standard stationary phase, which only allowed the separation of the entire group of (5-lactams from other non-(3-lactam analytes (e. g., bacitracin), the MIP enables the separation of the imprinted species from the pair of non-imprinted 3-lactams penicillin V and penicillin G see Fig. 6 [29,30]. 

Penicillins are the most widely used of the clinical antibiotics. They contain in their structures an unusual fused ring system in which a four-membered P-lactam ring is fused onto a five-membered thiazolidine. Both rings are heterocyclic, and one of the ring fusion atoms is nitrogen. These heteroatoms do not alter our understanding of molecular shape, since we can consider that they also have an essentially tetrahedral array of bonds or lone pair electrons (see Section 2.6.3). 

Structural modification of an existing molecule to improve its therapeutic value, e.g., by making it more effective, less toxic, better absorbed, or longer acting (such modification can also lead to the discovery of a new pharmacologic action, as in point 2 above, or of new therapeutic effects in man, as in point 5 below). An instructive example of the major therapeutic advances that have been obtained by molecular modification is seen in the family of penicillins that followed benzyl penicillin, the original member of the series. In little more than a decade from its first characterization, the original benzyl penicillin molecule was... 

---