Discovery of New Compounds in Nature1

COMPOUNDS made by living creatures, especially the small molecules with pronounced biological activity, are some of the most remarkable objects on earth. They embody lessons about the diversity of molecular structures, about nature's strategy of creating small molecules, and about the ways that small molecules influence biological processes. These lessons have informed and inspired a large part of organic chemistry. They have also provided biologists with tools to probe and understand biological function with extraordinary precision, and they have given pharmacologists and physicians a significant fraction of modern therapeutic agents. Naturally occurring small molecules, or their derivatives, are significant contributors to new drugs (60% of new cancer drugs and 75% of new anti-infectives from 1981 to 2002) and are well represented among the top-selling pharmaceutical agents. A few examples of these remarkable molecules are shown in figure 1. While biologically active small molecules have been isolated from many sources, the molecules in figure 1 are all produced by microorganisms that live in soil, and small molecules from soil microbes have made the greatest contribution to therapeutic agents. The bacterial realm of life has much greater genetic diversity than the more familiar eukaryotic realm of plants and animals. For example, two common bacteria, Eschericia coli and Bacillus subtilis, are genetically more distant from each other than humans are from corn. Different groups of bacteria produce different types of molecules. The actinomycetes, a group of grampositive bacteria characterized by branching filaments that resemble the mycelia of filamentous fungi, produce rapamycin, staurosporine, and dynemicin, among many others. Rapamycin, which was first found from a microbe in a soil sample collected on Easter Island, was discovered because of its antifungal activity. Today it is used to prevent the rejection of transplanted organs and is being studied as a treatment for cancers. The other molecules in figure 1 have similar histories and possible uses. Staurosporine was the first compound to show that partially selective kinase inhibitors could be discovered (or invented), and while its promiscuity for various kinases limited its clinical utility, it paved the way for the recently introduced anticancer agents such as Gleevec and Iressa. Dynemicin is one of the "enediyne" class of antitumor antibiotics, and its mode of action-a spectacular molecular rearrangement that yields a potent DNA-damaging agent-is found in a small family of very cytotoxic compounds. Versions of enediynes that are targeted to home in on cancer cells are currently in clinical trials as anticancer agents. A derivative of epothilone B, which comes from a myxobacteria or slime mold, is also in clinical trials as an anticancer agent. Saxitoxin and crytophycin, which are both produced by cyanobacteria (blue-green algae), are used to probe ion channels in nerve cells and as a possible anticancer agent, respectively. The last two, myxin and a homoserine lactone, are from the large class of Proteobacteria. Homoserine lactone is a signaling molecule that bacteria use to measure their cell density, and myxin is a broad-spectrum antibiotic. These are just a few of the many valuable molecules produced by soil-dwelling bacteria. Ironically, while we know a lot about these molecules and their actions in mammalian systems, we know much less about their natural role. Why, for example, does a soil-dwelling microbe on Easter Island make a molecule with an exquisite ability to disrupt human cell signaling? The usual answer, based more on belief than experiment, is that such molecules serve a defensive (or offensive) function and contribute to the survival of the producing species. Rapamycin prevents the growth of fungi by altering a fungal signaling pathway to trigger a starvation response. As the fungi hunker down, metabolically speaking, to await better times, the bacterial producer has one less competitor for nutrients. …