chapter  17
42 Pages

Contributions of Pharmaceutical Antibiotic and Secondary Metabolite Discovery to the Understanding of Microbial Defense and Antagonism

ByGerald Bills, David Overy, Olga Genilloud, Fernando Peláez

Metabolites Remain Unknown .................................................................................................... 267 17.5.1 Fungal Metabolites ......................................................................................................... 269 17.5.1.1 Ergotamine ..................................................................................................... 269 17.5.1.2 β-Lactams .............................................................................................269 17.5.1.3 Statins ............................................................................................................. 270 17.5.1.4 Cyclosporines and Mycophenolic Acid .......................................................... 271 17.5.1.5 Strobilurins ..................................................................................................... 272 17.5.2 Actinomycete Metabolites .............................................................................................. 272 17.5.2.1 Actinomycin D (Dactynomycin) ..................................................................... 273 17.5.2.2 Streptomycin and Other Aminoglycosides ......................................................274 17.5.2.3 Erythromycin .................................................................................................. 275 17.5.2.4 Vancomycin and Teicoplanin ......................................................................... 276 17.5.2.5 Amphotericin B and Other Polyenes .............................................................. 276 17.5.2.6 Rapamycin and FK506 ................................................................................... 278 17.5.2.7 Avermectin ...................................................................................................... 278 17.5.2.8 Streptogramins................................................................................................ 278 17.6 Horizontally Transferred Fungal Endophytes: Exemplary Opportunities

to Understand the Natural Roles of Antibiotics .......................................................................... 279 17.6.1 Echinocandins and Pneumocandins ............................................................................... 280 17.6.2 Enfumafungin, Arundifungin, and Other Acidic Triterpenes ....................................... 281 17.6.3 Sordarin and Sordarin Analogs ...................................................................................... 283 17.6.4 Apicidin, HC-Toxin, and Other Tetrapeptide HDAC Inhibitors .................................... 283 17.6.5 Nodulisporic Acids ......................................................................................................... 284 Acknowledgments .................................................................................................................................. 285 References .............................................................................................................................................. 285

The mention of defensive microbial mutualism immediately brings to mind the popular visions of antibiosis and intermicrobial warfare. Antibiotics were originally de ned as microbially produced secondary metabolites that inhibit the growth (static) or kill (cidal) other microorganisms. In the health care sci ences, this de nition has been expanded to also include semisynthetic and synthetic compounds. However, the scope of this chapter encompasses the fungi and bacteria and their small molecules that perturb, modify, or inhibit the growth, behavior, or physiology of other organisms. It has been hypothesized that during the early biochemical evolution, precursors of these secondary metabolites had a metabolic role in modulating macromolecular functions in the producer (Davies, 1990). All small molecules made by microorganisms, including antibiotics, are thought to have biological functions, even though in most cases, the function is unknown. Furthermore, we now know that organisms have dedicated a signi cant portion of their genomes to producing such compounds because of the selective advantages conferred upon them as a result of the interactions of the compounds with other organisms (Vining, 1990; Stone and Williams, 1992; Demain and Fang, 2000). Different variations of these hypotheses have been termed as the “competition” or “function-evolution” hypothesis (Wiener, 1996; Wink, 2003). However, counter viewpoints, termed as the “screening hypothesis” or the “diversity hypothesis” (Firn and Jones, 2003; Fischbach and Clardy, 2007) are based on the assumption that molecules with potent biological activity evolve infrequently and that selection occurs for organisms that synthesize multiple molecules from a given pathway because the probabilities of making an advantageous one with potent biological activity are increased.