Shape-shifting carbon ring helps researchers test alternative weed management tactic

A compound designed and synthesised by researchers in Australia can stop an invasive plant known as rubber vine from growing for six weeks. The work sheds new light on the little-studied process of herbistasis and explores how researchers could remodel existing herbicides as herbistatic agents.

Many weed species are developing resistance to herbicides, making them less effective. Inducing herbistasis to pause weed growth could be an alternative means to manage weeds, however, scientific understanding of the concept is limited, with only four previous examples identified.

Now, a team led by Craig Williams at The University of Queensland has created a fifth, cyclooctatetraene-metsulfuron methyl. They made it by furnishing the already used and understood herbicide, metsulfuron methyl, with cyclooctatetraene, a phenyl ring bioisostere.

Metsulfuron methyl prevents plant growth by targeting acetolactate synthase to block branched chain amino acid synthesis. ‘Our thinking here is that many known modes of action are already well established, therefore is it possible to utilise these more as opposed to potentially writing them off completely,’ says Williams. Rather than replacing herbicides, he envisions herbistatics becoming an additional chemical control against weeds.

‘It displays very interesting biological properties,’ says Williams on his choice to use cyclooctatetraene. ‘And is in constant dynamic equilibrium – shape shifting – and thus engages enzyme and receptor active sites differently to that of a static molecular moiety.’

To test the herbistatic effect, the researchers treated rubber vine (Cryptostegia grandiflora) with cyclooctatetraene-metsulfuron methyl. The plants only began growing vertically again eight weeks post-treatment, after which growth continued until the end of the experiment. Mortality was also lower in these plants, compared with plants treated with the herbicide metsulfuron methyl.

Having confirmed the herbistasis was reversible, the team also wanted to understand the compound’s underlying mechanism. Kinetic and binding studies of acetolactate synthase from Arabidopsis thaliana showed that the mode of action, acetolactate synthase inhibition, is the same for metsulfuron methyl and cyclooctatetraene-metsulfuron methyl but their mechanisms of action differ. From molecular docking studies, the team inferred that cyclooctatetraene prevents the aromatic ring of metsulfuron methyl from fully slotting into the enzyme. This means binding is weaker and it is freer to move in or out of the binding channel, causing a less harmful decrease in branched chain amino acid synthesis than with metsulfuron methyl.

Whether other herbicides can easily be adapted into herbistatics remains unclear. ‘The jury remains out on that question, because cyclooctatetraene-metsulfuron methyl is one of only a few synthetic herbistatic agents ever made. Hence, more examples will need to be explored to further our understanding in this space,’ says Williams.

David Barber, a lab leader in the Crop Science division at Bayer in Germany, highlights that the study is a good proof of concept on how cyclooctatetraene can be leveraged in other herbicides. ‘It is sure to generate a lot of attention from the crop protection research and industry communities, as well as promoting further research in the field with its thought-provoking conversion of a herbicide to a herbistatic agent.’

Williams speculates that restricting growth rather than attempting to kill a weed might ease the selective pressures that result in resistance. ‘In essence a herbistatic could trick the weed into not undergoing active site mutation,’ explains Williams. He says testing this theory would be an interesting next step to explore.