Metabolite discoveries, antibacterial

Table VI. Ranking of Approaches to Increased Antibacterial Microbial Metabolite Discovery 1970—1979...

Reichling J (2010) Plant-microbe interactions and secondary metabolites with antibacterial, antifungal and antiviral properties. In Wink M (ed) Functions and biotechnology of plant secondary metabolites, 2nd edn, Aimual plant reviews, vol 39. Wiley-Blackwell, Chichester Li JW, Vederas JC (2009) Drug discovery and natural products end of an era or an endless frontier Science 325 161—165... 

A search for antimetabolites, i.e. analogues of essential metabolites that might displace the latter in vital processes, was proposed as a rational approach to the discovery of antibacterial agents, but it has had little success other than the achievements in the folic acid field (Section 1.06.6). Substances that resemble the components of nucleic acids have, however, had considerable success in the chemotherapy of cancer and of some virus diseases and in the suppression of the immune response. They may act by becoming incorporated in false nucleic acids or by blocking the synthesis of nucleic acids, nucleotides, nucleosides or of the pyrimidine and purine bases cytosine (88), thymine (89 R = Me), adenine (90) and guanine (91 X = CH). The simplest antimetabolites are analogues of these bases. 

The screening of natural products became highly popular following the discovery of penicillin from a mould. Plants, fungi, and bacterial strains were collected from all round the world in an effort to find other metabolites with useful biological activities. This led in particular to an impressive arsenal of antibacterial agents (Chapter 9). Screening of natural products from plant and microbial sources continues today in... 

Clearly, the felicitous combination of technical factors which facilitated the initial burst of microbial metabolite drug discoveries no longer operates with the same effect. This has led to a judgment on the part of some that no important new antibacterial drugs or drug classes will be derived directly from microbiological sources in the future. 

The first section of the questionnaire probed the causes for the drop in the discovery rate of useful new antibacterial microbial metabolites, then sought judgments as to whether, and if so how, this trend could be reversed. Finally it asked the respondents to rate the potentialities of five discovery approaches for providing useful new antibacterial drugs over the next decade. 

These statistics point up a fact that may not be generally appreciated while the discovery rate for antibacterial microbial metabolites reaching general use in human or veterinary medicine has indeed dropped sharply, the total number of antibiotics discovered annually has not decreased. 

Proposals Designed to Increase the Discovery Rate of Antibacterial Microbial Metabolites. The questionnnaire cited five specific approaches that have been advocated as means of increasing the rate at which discoveries of significant new antibacterial antibiotics are made. The panel was asked to evaluate the validity of each approach separately, then to rank these five approaches in order of their practical potentiality for increasing the rate of discovery. . . over the next decade. Table VI lists these approaches and summarizes the responses. The two approaches... 

As the discovery rate of clinically accepted antibacterial microbial metabolites has fallen, that for microbial metabolites having other types of useful biological activity has remained at a fairly constant level (Table X). Examination of the structures of the microbial metabolites whose primary use is not as chemotherapeutic antibacterial agents shows that most do not belong to any of the major structural classes of antibacterial antibiotics. Furthermore, representatives of useful new classes have been discovered within the past decade. New structures will be found when microbial fermentations are tested for new types of biological activity. 

Following the discovery that the antibacterial sulfonamides were competitive antimetabolites of an enzymatic substrate (see subsequent discussion), there began what was thought to be a whole new direct approach to rational drug design of chemotherapeutic agents, namely, the structural modification of other essential bacterial and mammalian metabolites, particularly vitamins and amino acids. 

There are antagonists of the biosynthesis of dihydrofolic acid, and antagonists of its utilization. The history of the discovery of the antibacterial sulfonamides, typical antagonists of biosynthesis, was given in Sections 2.1 and 6.3.1. In 1940, Woods showed that the anti-bacterial action of sulfanilamide depended on its competition with j -aminobenzoic acid (P.7), which is a natural metabolite (Woods, 1940). Later this competition was shown to take place at the site on the enzyme dihydrofolate synthetase, which uses j -aminobenzoic acid to build up the molecule of dihydrofolic acid (2.74) (G.M. Brown, 1962). 

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