Developing a new resource for drug discovery: marine actinomycete bacteria William Fenical & Paul R Jensen Natural products are both a fundamental source of new chemical diversity and an integral component of today’s pharmaceutical compendium. Yet interest in natural-product drug discovery has waned, in part owing to diminishing returns from traditional resources such as soil bacteria. The oceans cover 70% of the Earth’s surface and harbor most of the planet’s biodiversity. Although marine plants and invertebrates have received considerable attention as a resource for natural- product discovery, the microbiological component of this diversity remains relatively unexplored. Recent studies have revealed that select groups of marine actinomycetes are a robust source of new natural products. Members of the genus Salinispora have proven to be a particularly rich source of new chemical structures, including the potent proteasome inhibitor salinosporamide A, and other distinct groups are yielding new classes of terpenoids, amino acid–derived metabolites and polyene macrolides. The continued development of improved cultivation methods and technologies for accessing deep-sea environments promises to provide access to this significant new source of chemical diversity. Natural products remain either the source of or the inspiration for a significant proportion of the new small-molecule chemical entities introduced as drugs 1 . From the detection of the antibiotic proper- ties of penicillin by Alexander Fleming in 1928, through the “golden age” of antibiotics and into the late twentieth century, the promise of unprecedented structural diversity and potent biological activ- ity from microbial secondary metabolites remained powerful forces driving pharmaceutical discovery. However, drug discovery strategies changed in the 1990s as techniques in combinatorial chemistry, high- throughput screening, and computer-assisted design of small-molecule ligands created alternatives to traditional drug discovery paradigms 2 . Yet like many trends, concepts in drug discovery that were once con- sidered passe have reemerged in a new light, and the unique structural diversity inherent to natural products is again being recognized for its value to the drug discovery process 3 . This renewed interest comes at a time when it is widely perceived that the pipeline for new antibiotics is running dangerously low 4 . It is also a response to the realization that bacterial diversity has not been efficiently explored and, perhaps more importantly, that major environmental habitats have yet to be sampled with natural-product discovery in mind. Given the vast area of the world’s oceans (70% of the Earth’s sur- face), it is at first thought surprising that the extensive drug discovery efforts involving soil bacteria have not been extended to this ecosys- tem. However, sampling the ocean’s diverse habitats requires specialized equipment and, in the case of deep ocean environments, the develop- ment of new technologies. During the period in which soil bacteria (especially the actinomycetes) were being used for drug discovery, it was proposed that most important groups of drug-relevant bacteria are not indigenous to the ocean 5 . In the 1950s the very existence of marine bacteria was questioned 6 . Couple these ideas with the wide- spread observation that <1% of the bacteria in the ocean form colonies on traditional nutrient agar media 7 and it becomes clear that there has been little motivation to examine this potentially massive resource. We now know that the oceans are a highly complex microbiological environment with typical microbial abundances of 10 6 per ml in sea- water and 10 9 per ml in ocean-bottom sediments. As DNA sequence- based methods are applied to the field of marine microbial ecology, we are now beginning to comprehend just how complex, exquisitely unique and highly adapted these organisms are 8 . Although the biology of marine bacteria is beginning to be understood, the chemical activi- ties of these organisms remain largely unexplored. In this Perspective, we provide highlights from our chemical studies of sediment-derived marine actinomycetes as well as key discoveries from other groups working in this field (see ref. 9 for additional details). Actinomycetes in the sea Bacteria within the order Actinomycetales (that is, the actinomycetes) are common soil inhabitants with an unprecedented ability to produce clinically useful antibiotics. Though more than 50% of the microbial antibiotics discovered so far originate from actinomycete bacteria, only a few select soil-derived genera (Streptomyces and Micromonospora) account for most of these compounds 10 . It has long been recognized that actinomycetes can be recovered from the sea 11 and, more recently, the deepest known ocean trenches 12 . However, it is less clear whether these marine-derived strains are meta- bolically active or adapted to life in the sea. The isolation of actinomy- cetes could be accounted for by the cultivation of spores (originating from soil-inhabiting strains) that have been washed into the marine environment. This concern has led to questions regarding the existence of marine actinomycetes and whether or not marine-derived strains are metabolically active in the sea 5 . Certainly these questions were of William Fenical and Paul R. Jensen are at the Center for Marine Biotechnology and Biomedicine, Scripps Institution of Oceanography, University of California, San Diego, La Jolla, California 92093-0204, USA. e-mail: wfenical@ucsd.edu Published online 15 November 2006; doi:10.1038/nchembio841 666 VOLUME 2 NUMBER 12 DECEMBER 2006 NATURE CHEMICAL BIOLOGY PERSPECTIVE © 2006 Nature Publishing Group http://www.nature.com/naturechemicalbiology