ABSTRACT
SummaryOriginal molecules from nature provide templates which can be scaled up or modified to make better drugs through chemistry, biology and allied sciences. Molecular diversity from combinatorial and diversity-oriented chemical synthesis provides even wider selections. Fragment-based drug discovery shows the power of making effective drugs from components, each of which may bind only weakly to the target. Combinatorial biosynthesis provides a method for producing ‘nonnatural’ natural products, while metagenomics can lead to the discovery of new antibiotics, even from microorganisms which cannot be grown. Rules governing the ability of drug molecules to act effectively, including surviving long enough in the host and accessing tissues and targets of action, can be
used to build better platforms for development of new drugs from original natural molecules. 4.1 Expanding the Potentials of Molecular
WildernessAlthough the range of molecular wilderness is vast in giving us drugs against various ailments, there are limitations which need to be overcome in order to realize its full potential. Take the case of antibiotics, natural products produced by microbes, plants and other organisms against other microbes which are pathogens. At least three main problems were encountered from the beginning of their discovery. First, the quantities of antibiotics produced in nature are small and normally insufficient to meet the demand for human therapeutic use, especially in their extraction and purification from natural sources. Industrial production of these antibiotics needs to be devised in order to enable them to have widespread use. The best microbial or other sources of antibiotics need to be found. Fermentation technologies for the production of drugs also need to be developed. The history of the production of penicillin provides a lesson of how these problems were overcome [54, 55]. After the chemical nature of the compound was established and definitive proof of its value in treating infections was obtained, effort was undertaken to find the best source of the Penicillium mould and to develop the fermentation process which would yield large amounts of the drug. This was accomplished just in time for the large demand as the Second World War reached a peak before its end. Penicillin made a major difference in reducing wound infections and therefore the number of deaths and amputations resulting from the war. Today, industrial production of antibiotics in penicillin and other families by fermentation makes use of optimized strains of producing microorganisms, often with gene replacements for more effective production, and the processes are highly automated for control of various contributing factors [56]. Many drugs from plants have to be harvested from their natural sources, which can be tedious and expensive. Some plants or parts thereof, from which the products are derived, have to be supplied
from their natural sources, posing threats to environmental sustainability. Others which can be harvested from suitable plantations can impose a high cost on production. Paclitaxel (Taxol) is an anticancer drug derived from endophytic fungi in the bark of the Pacific yew tree. However, it has been estimated that treating a patient would require the consumption of eight 60-year-old yew trees [57]! Such high environmental and financial costs must be avoided in an attempt to obtain new drugs from nature. Secondly, although antibiotics from nature, like penicillin, are very effective against a number of infectious organisms, they have a narrow spectrum of activity; namely, they are only effective against a limited range of such organisms. The mechanism of action of penicillin (see Box 4.1) provides a way to expand the spectrum of action through chemical modification of the drug to make semisynthetic penicillins, which have better properties, such as greater accessibility to the microbial pathogens inside the host and an ability to treat a wider variety of infections, including penicillin-resistant infections. The key step to semisynthetic penicillins is the production of 6-aminopenicillanic acid (6-APA), which retains the beta-lactam function necessary for efficacy and is the nucleus for adding other chemical groups which give additional properties to the semisynthetic drugs. Synthetic modification of natural products derived from plants can also result in new drugs with enhanced qualities, such as artesunate, an antimalarial modified from artemisinin extracted from the Artemisia plant, with higher solubility and better oral bioavailability. Thirdly, the chemical diversity of antibiotics needs to be expanded so as to increase the ability to deal with various infectious diseases. The pioneering work of Selman Waksman, who coined the term ‘antibiotics’, led to the discovery of streptomycin from Streptomyces bacteria [27]. General methods for screening microorganisms for the presence of useful antibiotics were developed, which led to the discovery of many more antibiotics with various modes of action. At present, microorganisms from soil and various sources in the environment have been screened exhaustively by various groups of researchers and drug companies. New antibiotic discoveries have become increasingly rarer after the first few decades since the 1940s, and so new sources need to be tapped, including the deep oceans and other hard-to-reach locations.
