For a long time, I had assumed that the AMES test was an abbreviation and that it was one of the most brilliant transformations of a surprising insight into something useful. I was delighted and envious when I discovered that this clever trick was actually named after its inventor, Bruce Ames. In this test for mutagenicity, a range of bacterial strains that have naturally occurring mutations preventing them from synthesising a specific amino acid (usually histidine) are grown in media lacking that amino acid. Exposure to certain types of mutagen cause reversion to a form that is able to synthesise the amino acid and hence the bacteria can grow and reproduce leading to the appearance of colonies on the plates (Figure). The details of the test, including some of its history, are described in this article by Mortelmans and Zeiger. The paper is a veritable manual for those wishing to run the test with troubleshooting and detailed instructions for all procedures provided. One of the key challenges is that many compounds are not mutagenic until they are metabolised and so the test requires the inclusion of some form of metabolic system and the choice of this can be critical. There remains much debate about the reproducibility and relevance of the Ames test but it has been a crucial defence in pre-clinical screening.

Ames cells

The Salmonella (Ames) test for mutagenicity
K Mortelmans, E Zeiger

Current protocols in toxicology Curr Protoc Toxicol. 2001 May;Chapter 3:Unit3.1.

Among many others, I’ve shown how results in the Ames test for aromatic amines (a common mutagen class) can be correlated with simple chemical descriptors and that this can be used to design safer compounds (doi: 10.1021/jm3001295), McCarren and colleagues and Novartis have shown that this approach likely has a dependence on the size of the molecule (doi: 10.1016/j.bmc.2011.03.066) and Shamovsky and colleagues at Astrazeneca (doi: 10.1021/acs.jmedchem.1c00514) have probed the metabolic process and this may relate to the molecular weight limit already mentioned. The beauty of this area is that unlike much that is utterly mysterious about biology when looked at by chemists, mutagenicity often has a strong chemical component that be rationalised and predicted.

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