Prototype antibiotics

Cephalosporins display an antibiotic mechanism of action identical to that of the penicillins. Cephalosporin C (Figure 1.14) is the prototypic natural cephalosporin and is produced by the fungus Cephalosporium acremonium. Most other members of this family are semi-synthetic derivatives of cephalosporin C. Chemical modification normally targets side-chains at position 3 (the acetoxymethyl group) or 7 (derived from D-a-aminoadipic acid). 

The cephalosporins, discovered in the 1950s, are produced by various species of the mold Cephalosporium. Cephalosporin C (9.46) is the prototype of these antibiotics, and its structure shows a close similarity to the penam stmcture. The 5-thia-l-azabicyclo[4.2.0] octane ring system is therefore called the cepham ring. The parent compound carries the aminoadipate side chain, which can be cleaved to supply the 7-amino-cephalosporanic acid. This amine can easily be acylated and thus forms the basis of many useful derivatives. The 3-acetoxymethyl substiment is also amenable to modifications. 

The antipsychotic chlorpromazine is a prototype heptotoxicant for production of cholestasis. Pleiotropic effects of chlorpromazine on membrane permeability and associated ion gradients and microfilament-mediated canalicular contraction have been attributed to detergent effects. Valproic acid, an anticonvulsant, is associated with microvesicular steatosis. Inhibition of mitochondial fatty acid (S-oxidation is an important component of this toxic effect and is apparently related to carnitine availability as evidenced by the protection afforded by L-carnitine supplements. The hypolipidemic drugs clofibrate, fenofibrate, and gemfibrozil are peroxisome prolif-erators in rodent liver, but not in humans. Isoniazid, an antibiotic used to treat tuberculosis, exhibits an approximately 1 % incidence of hepatotoxicity. Although toxicity is known to be metabolism-dependent and protein adduction has been well-... 

An important family of inhibitors of procaryotic RNA synthesis are the antibiotics of the ansamycin series whose prototype is rifampicin. It inhibits bacterial RNA synthesis at the extremely low concentration of 0.01 Mg/ml (1.4 x 10-8 M) by binding to bacterial RNA polymerase35. ... 

A second category of membrane-active antibiotics are the depsipeptides with valinomycin as the prototype. These substances act as iononophores and increase permeation of K+ ions. The antibacterial effect of 10 6 M valinomycin can be reversed by supplying an excess of K+ 6°). 

The prototypical aminoacylated nucleoside analogue antibiotic is puromycin which inhibits the protein translation in all three domains of life. The chemical structure of puromycin is the same as that of tyrosylated adenosine, except for the presence of three added methyl groups and the replacement of an ester bond with an amide bond (Fig. 4.11). Puromycin mimics tyrosyl-tRNA so well that it binds to the A-site and gets incorporated into an elongating peptide. This leads to termination of translation because puromycin terminated peptides fall off the ribosome. Puromycin derivatives have been used crystallographically as peptidyl transferase substrates and have contributed to our understanding of the structure of the peptidyl transferase site (Fig. 4.5) [11, 16, 45],... 

The prototypical lantibiotic, nisin, was discovered in 1928 for its antibacterial properties and has been used as a preservative in dairy products since the 1950s (1). Nisin and other lantibiotics exhibit nanomolar efficacy against many Gram-positive strains of bacteria (2), which include methicillin resistant Staphylococcus aureus, vancomycin resistant enterococci, and oxacillin resistant bacteria. On the other hand, some lantibiotics function as morphogenetic peptides rather than antibiotics and are important for spore formation in streptomycetes (3). Since the structural elucidation of nisin in the early 1970s, extensive research efforts have been directed at understanding the biosynthesis and mode of action of various lantibiotics. 

Tylosin (13) Figure 5.6) is the prototype of the second large division of 16-membered macrolides, based upon differences from the leucomycins in aglycone structure. Tylosin is an important veterinary antibiotic produced... 

Sun, D., M. Hansen, J.J. Clement, and L.H. Hurley (1993). Structure of the altromycin B (N7-gua-nine)-DNA adduct. A proposed prototypic DNA adduct structure for the pluramycin antitumor antibiotics. Biochemistry 32 8068-8074. 

The rational bases for the expectation that examination of microbial fermentations can provide important new antibacterial antibiotic discoveries have already been explored. For some of the respondents there is also an element of faith involved. What is expected is not rebirth of the era of prolific discoveries but the isolation and recognition in the next decade of a few significantly improved congeners of antibiotics already in use, a few antibiotics belonging to new structural classes which will have important therapeutic advantages, and a few new prototype structures worthy of chemical modification. 

Scheme 19.5 Landmark experiment leading to the birth of the sulfonamide antibiotics. Prontosil, 5, is itself inactive but upon oral administration 5 is metabolized by gut microflora to 6, sulfanilamide, which exhibits excellent activity against streptococcal infections. 6 has gone on to become the prototypical sulfonamide antibiotic from which numerous other successful antibiotic drugs have been designed.

Daunorubicin (1) and doxorubicin (2), the prototypes of anthracycline antibiotics, were isolated from various Streptomyces strains and early introduced into the clinic for cancer chemotherapy. Despite considerable... 

Linezolid Antibiotic (prototype oxazoladinone) binds to SOS ribosomal subunit to in-... 

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