Natural antibiotics

Lactic acid-producing bacteria associated with fermented dairy products have been found to produce antibiotic-like compounds caUed bacteriocins. Concentrations of these natural antibiotics can be added to refrigerated foods in the form of an extract of the fermentation process to help prevent microbial spoilage. Other natural antibiotics are produced by Penicillium wqueforti the mold associated with Roquefort and blue cheese, and by Propionibacterium sp., which produce propionic acid and are associated with Swiss-type cheeses (3). 

Knowledge of the mechanism of action and investigations on the physico-chemical characteristics of the therapeutically used dalbaheptides has stimulated the transformation of natural antibiotics into new derivatives using both chemical and biosynthetic modification. 

In addition, several oj-hydroxyacids have been prepared. The systems prepared by Yamazaki (8) have been evaluated for ion transport action. Those prepared at Upjohn have been reported to have Ca activity comparable to the natural antibiotic X-537A (9) and to be more active than crown ethers. The most active of their structures is shown as 10. 

The thiophene analog of chloramphenicol (255) has been synthesized,as also have been similar structures. The antibacterial activity of all was much lower than that of the natural antibiotic. The thioamide of 2-thenoic acid has been prepared in a study of potential antitubercular compounds. It did not surpass thioisonico-tinamide in antitubercular activity. The thiosemicarbazones of thio-phenealdehydes and ketones (cf. Section VII,D) show high activity against Mycobacterium tuberculosis, but are very toxic. The thiosemi-carbazone of 4-(2-thienyl)-3-buten-2-one has been reported to be capable of completely inhibiting the in vitro growth of M. tuberculosis even in relatively low concentrations. ... 

Monensin, which is one of the natural antibiotics, selectively transports Na+ across an artificial liquid membrane (organic solvent) from the basic aqueous phase (IN) to the acidic aqueous phase (OUT), driven by the proton gradient8). (Fig. 1, 2)... 

Epimerization of 4 at C-2 provided 5a-carba-a-DL-galactopyranose (6). When the pentaacetate IS was heated in acetic acid containing sulfuric acid, epimerization occurred at C-2 through an intermediary cyclic acetoxonium ion (18), with anchimeric assistance of the vicinal, axial acetoxyl group. After acetylation, 5a-carba-a-DL-galactopyranose pentaacetate (19) was obtained in a yield of 14% it was converted into 6 by hydrolysis. The antimicrobial activity of the racemate 6 was found to be about half that of the natural antibiotic 7 in the same assay system, indicating that the L-antipode is probably inactive. " ... 

It is now recognised that a wide range of organic molecules, collectively termed ionophores 185,186) or complexones 187), are able to facilitate ion (usually cation) transport. Two major mechanisms have been revealed for this process, namely the involvement of transmembrane ion carriers and transmembrane pores or channels (see Fig. 19). The majority of ionophores studied to date are natural antibiotics and their synthetic analogues which are, on a biological scale, comparatively small molecules lending themselves to study outside the biological system. In contrast far less is known about the molecular structures involved in normal transport processes. Such molecules are likely to be more complex or present in small amounts and may require... 

A microwave assisted Comforth rearrangement of oxazole-4-carboxamides 106 efficiently afforded 5-aminooxazole-4-carboxylates 107. This procedure was applied to the formal synthesis of a natural antibiotic derived from pseudomonic acid <06TL4698>. 

The crowns as model carriers. Many studies involving crown ethers and related ligands have been performed which mimic the ion-transport behaviour of the natural antibiotic carriers (Lamb, Izatt Christensen, 1981). This is not surprising, since clearly the alkali metal chemistry of the cyclic antibiotic molecules parallels in many respects that of the crown ethers towards these metals. As discussed in Chapter 4, complexation of an ion such as sodium or potassium with a crown polyether results in an increase in its lipophilicity (and a concomitant increase in its solubility in non-polar organic solvents). However, even though a ring such as 18-crown-6 binds potassium selectively, this crown is expected to be a less effective ionophore for potassium than the natural systems since the two sides of the crown complex are not as well-protected from the hydro-phobic environment existing in the membrane. 

In addition to chemical-based drugs, a range of pharmaceutical substances (e.g. hormones and blood products) are produced by/extracted from biological sources. Such products, some major examples of which are listed in Table 1.2, may thus be described as products of biotechnology. In some instances, categorizing pharmaceuticals as products of biotechnology or chemical synthesis becomes somewhat artificial. For example, certain semi-synthetic antibiotics are produced by chemical modification of natural antibiotics produced by fermentation technology. 

Michael additions to sugar nitro olefins have received considerable less attention than the Henry reaction involving nitro sugars. Early examples of Michael addition include the synthesis54 of licoricidin by Paulsen in 1982, the addition of phosphorous nucleophiles to a D-glucose based nitro olefin55 by Yamashita in 1987 and the synthesis of the natural antibiotic polyoxin published by Barret in 1990.56... 

For a more extensive discussion of the kinetics of complexation with cryptands and natural antibiotics, the reader is referred to a recent review of Liesegang and Eyring (1978). 

Despite the many limitations, the Dotz benzannulation remains a powerful tool for the preparation of substituted phenols. One example of the use of a Dotz benzannulation as the key step in a synthesis of the potent natural antibiotic fredericamycin A (as racemate) is sketched in Figure 2.26. 

Aldehydes and ketones were used in many syntheses starting from an AA. The first total synthesis of porothramycin B, a potent natural antibiotic, used l-G1u as starting material. In the first step compound 31 was obtained from an A -protected A A and paraformaldehyde (84TL927 88TL2231 93TL2577). 

Table VI. Natural Antibiotics Produced by Lactic Cultures...

The natural antibiotic novobiocin (Fig. 3) is an example of diversity enhancement by the combination of building blocks from different pathways, such as aromatic rings, isoprenoid, amino acid, and sugar components, finished by post-modification [22]. 

These conjugated natural antibiotics prompted the search for novel synthetic siderophores that contain a variety of drugs . 

More attention will be given to the AC s than to the AEC s. Furthermore, the discussion will bear principally on synthetic ligands. The very interesting natural antibiotic ligands have been discussed in other chapters (see pp. 86—96) their properties will be used here merely for illustration and comparison purposes since they are more difficult to analyze in terms of strategies because of their complicated structural features. 

Table 10. Stability constants (log Kt) of alkali and alkaline-earth metal cation complexes with some selected natural antibiotic ligands (K, in Imol i)...

There are a variety of natural antibiotics which contain a pyrimidine or reduced pyrimidine ring <2005CBI1>, and several of these are used therapeutically for a number of different applications. Blasticidin S and the polytoxins were mentioned in the section on antifungals, but other examples include amicetin, capreomycin, gougerotin, and viomycin, as well as the bleomycins and phleomycins. 

Reduction of the nitro group of 545-547 in the presence of Raney nickel catalyst respectively afforded the corresponding 4-amino-pento-, -hexo-, and -hepto-pyranosides 548-550. Methyl 4-amino-2,3,4,6-tetradeoxy-a- and -/3-DL-en/t/iro-hexopyranoside (549), characterized as the A -benzoyl derivative, was identical in its H-n.m.r.-speetral data with the analogous derivative of the natural, antibiotic sugar tolyposamine. On the other hand, reductive demethyl-ation of 549 with formaldehyde-Raney nickel (under 3.5 kg/cm2 pressure of hydrogen) was effected, to yield another antibiotic sugar, methyl DL-forosaminide (551). 

The cephalosporins are semisynthetic -lactams derived from cephalosporin C, a natural antibiotic. Their active basic nucleus consists of a six-membered dihydrothiazine ring fused to a -lactam ring (Fig. 3.3.2). Cephalosporins have some desirable quality characteristics that are generally deficient in penicillins. The popularity and usefulness of cephalosporins results from their resistance to many... 

A number of 1,2,4-triazines are of interest owing to their biological activity. 1,2,4-Triazine-3,5-diones (6) represent aza analogues of pyrimidine nucleic acid bases, a number of natural antibiotics are derivatives of pyrimido[5,4-e][l,2,4]triazine (7), and 4-amino-6-r-butyl-3-methylthio-l,2,4-triazin-5-one (8) and 4-amino-3-methyl-6-phenyl-l,2,4-triazin-5-one (9) are used as herbicides. 

Although oligomers of a-hydroxy acids (depsides) and mixed oligomers of cx-hydroxy and a-amino acids (depsipeptides) are found in nature (antibiotics, ion-transporters [249,250]), little solid-phase methodology has been developed for their preparation. One recent strategy is based on sequential acylation with THP-protected cx-hydroxy acids (DIC, DMAP, THF, 2 h see Entry 6, Table 13.13), followed by deprotection with TsOH/MeOH [249,251]. Under these conditions, no racemization was observed. A similar approach to the solid-phase synthesis of depsipeptides is outlined in Figure 16.24. 

Sutcliffe JA Improving on nature antibiotics that target the ribosome. Curr Opin Microbiol. 2005 8 534-542. 

Some appear to be natural antibiotics and anticancer agents... 

James T. Park (1922- ) and Jack L. Strominger (1925- ) demonstrate that penicillin blocks the synthesis of the peptidoglycan of bacteria. This represents the first demonstration of the action of a natural antibiotic. 

---