There are miniature natural product libraries to be found in the most unexpected places. Zoe Wilson and Margaret Brimble of the University of Auckland, New Zealand, delve deeper

A microorganism that survives extreme environments can be classified as either extreme-tolerant, if it grows best under more moderate conditions, or extremophilic, if it grows optimally under these extraordinary conditions. In order to survive in such settings, microorganisms have developed unique defences, and this has frequently led them to produce novel molecules. This has made them a mine for natural product chemists.  But whilst the first extremophilic organism was isolated in the 1860s, it took over a century for scientists to realise that the number of these organisms is significant, leading to a rapid growth in research in this area.

Traditionally, the extremes of life are considered to be high and low temperature (inhabited by thermophiles and psychrophiles respectively), high pressure (piezophiles/barophiles), high and low pH (alkaliphiles and acidophiles), and high salt (halophiles). Many extremophiles actually thrive in environments which are extreme in two or more aspects. For example, the Shewanella violacea strain DSS12, which produces a novel violet pigment, was isolated from the Ryukyu trench in the Philippine Sea, at a depth of 5110m. This bacterium is a barohalopsychrophile - growing optimally at 30MPa, 8°C and in the presence of 3 per cent sodium chloride.

To date the largest number of novel molecules from extreme dwelling microorganisms have been isolated from thermophiles. Several of these molecules are thought to play a role in survival at extreme temperatures, such as ether linked lipids, modified nucleosides and a variety of polyamines which are thought to stabilise DNA at high temperatures by reducing flexibility.

The term psychrophile was first used in 1902. Representatives of all the major taxa have been found inhabiting temperatures below 0°C, making this is one of the more diverse branches of the extremophiles. To date however the only novel molecules first isolated from psychrophilic or psychrotolerant microorganisms are secondary metabolites, which are largely based on modified peptides. These include mixirins A-C, three cyclic peptides isolated from the psychrotolerant Bacillus sp. strain MIX-62, which have been shown to inhibit human colon tumour cell growth.

Piezophiles (barophiles) are typically isolated from the bottom of the ocean and the majority of secondary metabolites isolated from these extremophiles are cyclic. Notably, a series of cyclic secondary metabolites that halt cell replication in mouse tsFT210 cells were isolated from Aspergillus fumigatus strain BM939, a fungus isolated from the sea bottom of the Oi river, Sizuoka prefecture, Japan. 

Halophiles have to survive osmotic stress. One survival mechanism they use is to accumulate small molecules known as osmolytes, with eight novel osmolytes being first isolated from halophilic or halotolerant microorganisms. 

Enzymes from alkaliphilic or alkali-tolerant microorganisms have made a large impact due to their industrial applications in biological detergents. But, to date, relatively few novel molecules have been isolated from these microorganisms. Among them are novel carbohydrates and an unusual lipid from bacteria of the Halomonas species.

Microorganisms capable of surviving low pH have been isolated from a range of sources around the world, both natural, for example acidic hot springs, and man-made, such as Berkeley Pit Lake (an abandoned copper mine which filled with acidic water). These microorganisms produce diverse secondary metabolites with a range of biological activities. For example, thirteen of the molecules isolated from Berkeley Pit Lake microorganisms inhibit protein-cleaving enzymes caspase-1 and matrix metalloproteinase-3.

When the large number of reported extremophiles is considered, very few have been screened for novel secondary metabolite production. Despite nearly 150 years in the public domain, this rich source of novel molecules remains largely untapped.

Read more in Wilson and Brimble's review 'Molecules derived from the extremes of life' in issue 1, 2009, of Natural Product Reports.