Microbial Secondary Metabolites Play Important Roles in Medicine; Prospects for Discovery of New Drugs

MICROBIAL SECONDARY METABOLITES PLAY IMPORTANT ROLES IN MEDICINE; PROSPECTS FOR DISCOVERY OF NEWDRUGS RONALD BENTLEY* In a previous essay, secondary metabolites were described as compounds not required for growth by the organism in which they are produced, and which are present only in restricted taxonomic groups [1, 2].1 They are especially prevalent in plants and microorganisms, and it is often difficult to discern any possible function for them in the producing organism. Despite the unfortunate adjective secondary, these compounds have had and continue to have profound implications for humanity. The earlier essay concentrated on plant secondary metabolites used as dyes, fragrances, psychotropic agents, and medicináis; dyes from mollusks and insects were also discussed [2] . In continuing a general review ofsecondary metabolites, this essay focuses on products from microorganisms and considers how useful new secondary metabolites may be discovered in all types of organisms. Secondary Metabolites as Antibiotics Some plant secondary metabolites will stain human skin (e.g., indigotin, lawsone), and alizarin yields a reddish-purple color to bone under certain conditions [2]. In the 19th century, the anatomistJoseph von Gerlach began to use plant dyes for visualization of various organelles in microscopic studies; he coined the phrase, "Arte tingendi innititur histológica" ("The art of staining is the basis of histology") [3] . As with dyes used for esthetic purposes, the vegetable dyes used in histology were quickly replaced by synthetic dyes which were extensively used by Paul Ehrlich, beginning in 1877. Of the seven synthetic dyes then described, one still had some con- *Department of Biological Sciences, University of Pittsburgh, Pittsburgh, PA 15260 The author is grateful to ProfessorJoan W. Bennett for helpful comments on an early draft of this essay. Thanks also to Suzanne C. Gardon (for a translation from French). 1 General information about compounds for which no citation is provided can be found in [I].© 1997 by the University of Chicago. All rights reserved. 0031-5982/97/4003-0990101.00 364 Ronald Bentley ¦ Secondary Metabolites as New Drugs nection with the natural world: this was purpurin, a hydroxy derivative of alizarin, which occurs as a glycoside in Rubia tinctorum roots, especially on storage. Ehrlich's pioneering work in experimental chemotherapy led to the development of the arsenic compounds salvarsan and neosalvarsan for treatment of syphilis and some other conditions. He traced this work back to his use of dyes: Although modern chemotherapy has established itself in science and medical practice , its origin goes back to the histological stainings; so it is no coincidence that the first chemotherapeutic experiments that ended so promisingly were conducted with dyes—methylene blue or trypan red. Initially, therefore, chemotherapy was a "chromotherapy." [3] The chemotherapeutic wheel has now come full circle—Ehrlich's work with the arsenicals was followed by the development of synthetic sulfonamides , which in turn were superseded by the antibiotics found in various microorganisms as secondary metabolites. s ArsenicalSulfonamides y chemotherapeutics ? t h e Histological stains t i C ? a t Plant secondary metabolitesMicrobial secondary metabolites u used in histology; various botanicalsused as antibiotics r used in medicine a I The antibiotic age began in 1940, when Florey's group at Oxford developed penicillin as a systemic therapeutic agent; this "queen of antibiotics" still occupies a preeminent position in medicine even after 50 years. As is well known, the antibiotic activity of culture fluids from a Pénicillium mold was discovered by Alexander Fleming in 1928. He used "mould juice" in therapy without providing any detailed records. Similar preparations were used in 1930 by Dr. C. G. Paine at the Royal Infirmary in Sheffield to treat eye infections [4] . Two clinical records of this work have survived and are "the earliest published recorded cures using penicillin where the evidence has been substantiated by case notes [5]. When penicillin was introduced into general medical practice, it appeared to many to represent a comPerspectives in Biology and Medicine, 40, 3 ¦ Spring 1997 | 365 pletely new approach to infectious disease, one that verged on the miraculous . However, as we are reminded: "The thing that hath been, it is that which shall be; and that which is done is that which shall be done: and there is no new thing under...