Bacterial natural products

Clardy, J., Fischbach, M.A. and Walsh, C.T. (2006) New antibiotics from bacterial natural products. Nature Biotechnology, 24, 1541. 

Owing to the fact that the primary source of antibacterial agents for biomedical applications are secondary metabolites and chemical derivates of actinomycetes, fungi, and certain soil bacteria such as myxobacteria, most of the recent advances in molecular engineering have been made in relation to polyketide and peptide antibiotics (e.g., erythromycin and vancomycin)24 Recent literature on this topic suggests a greater mechanistic diversity in biosynthetic potential of bacterial natural products that was believed previously. 

Figure 10 Other novel bacterial natural products discovered by genome mining.

Other approaches. There is also a less efficient multistep procedure first introducing a C3 substiment at N1 by reaction of the deprotonated indole with ethyl a-bromopropionate, followed by a-methylation and reduction to the hydroxy tert-butyl group, oxidation to the aldehyde and elongation to the tert-prenyl group by methylenation. This strategy was employed by Yao and co-workers in their synthesis of the marine bacterial natural product cyclomarin C [59,60] and by Spinella and coworkers for obtaining A(-tert-prenyl-3-methoxycarbonylindole [61],... 

Wenzel, S.C. and Muller, R. (2005) Recent developments towards the heterologous expression of complex bacterial natural product biosynthetic pathways. Curr. Opin. Biotechnol, 16 (6), 594-606. 

Subsequently, other structural variations were reported encompassing compounds such as PS-5 (5) (5), carpetimycin A (6) (6), asparenomycin A (7) (7), and pluracidomycin A (8) (8), from a wide variety of streptomycete strains. Following these stmctures the simplest member of the series, having the completely unsubstituted nucleus, (1, X = CH2), was isolated from bacterial strains of Serratia and Ervinia (9). AH other natural products reported have substituents at both the C-6 and C-2 positions of the bicycHc ring system. Differences in the nature and stereochemistry of these substituents has provided a wide variety of stmctures, and over forty variations have been reported and comprehensively Hsted (10). 

The study of biochemical natural products has also been aided through the application of two-dimensional GC. In many studies, it has been observed that volatile organic compounds from plants (for example, in fruits) show species-specific distributions in chiral abundances. Observations have shown that related species produce similar compounds, but at differing ratios, and the study of such distributions yields information on speciation and plant genetics. In particular, the determination of hydroxyl fatty acid adducts produced from bacterial processes has been a successful application. In the reported applications, enantiomeric determination of polyhydroxyl alkanoic acids extracted from intracellular regions has been enabled (45). 

Many powdered raw materials, e.g. china clay, talc and calcium carbonate are natural products, coming from the soil and often contaminated with appreciable numbers of bacterial and fungal spores. Products heated to high temperatures during preparation, e.g. calcined kaolin clay used as a titanium dioxide extender, will generally be free from such contaminants. 

Recently, a new natural product linking sulfur, oxygen and iron has been isolated from bacterial sources. These substances, the thiohydroxa-mic adds, are worthy of discussion in the present context even though their biological significance has yet to be defined. The copper and iron complexes of N-methyl thioformylhydroxamic acid were obtained from the culture broth of Pseudomonas fluorescens and named fluopsins C and... 

Moore, B.S. and Hertweck, C. (2002) Biosynthesis and attachment of novel bacterial polyketide synthase starter units. Natural Product Reports, 19 (1), 70-99. 

Epothilones A, B and E (4,5 and 6) (Fig. 2) are representative members of a new class of bacterially derived natural products which exhibit potent biological activity. Isolated by Hofle and coworkers [6] from a soil sample collected near the Zambesi river, the compounds have provided a great deal of excitement in the scientific community due to their potent cytotoxicity against a number of multiple drug-resistant tumor cell lines and because of the mechanism by which they exert this effect. Like Taxol [7], the epothilones promote the combination of a- and 3-tubulin subunits and stabilize the resulting microtubule structures. This mode of action inhibits the cell division process and is, therefore, an attractive strategy for cancer chemotherapy [7,8]. 

The use of BRMs to treat human disease has its origins in the use of bacterial toxins to treat cancer by William B. Coley.73 These early studies resulted in the use of microbi-ally-derived substances such as BCG, Picibanil, carbohydrates from plants or fungi such as Krestin and Lentinan, other products such as Biostim and Broncho-Vaxom, as well as thymic extracts (Table 9.4). However, the lot-to-lot variation in the manufacture of these drugs has dampened enthusiasm. Equally, the focus on MOAs in drug development strategies has also dampened developmental efforts. The particulate nature of some BRMs can also result in pulmonary thrombosis and respiratory distress following i.v. injection. However, BRMs are commonly used to treat bladder cancer and derivatives of natural products are routinely used clinically. 

Examples of successful natural product screens directed against proven targets include screens designed to look for inhibitors of bacterial cell wall biosynthesis. These screens were established once it became clear... 

A few thousand years before the word biotechnology was coined, vinegar had been obtained from the bacterial oxidation of the ethanol contained in natural products like wine, cider, or malt. A pure dilute solution of acetic acid can also be made by the same method when aqueous ethanol is the starting material. The net reaction is represented by ... 

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