A strange biological quirk is being exploited to deliver compounds with new molecular targets to industry

The crisis in medicine due to antibiotic-resistant bacteria may seem a strange place to begin a story about herbicides. But in a world of discovery that can prove unimaginably strange, it turns out that the killing power of antibiotics and herbicides can have a common molecular basis.

That is the finding being exploited by Dr Tatiana Soares da Costa and her team at the University of Adelaide. Their goal is to build a new herbicide development pipeline based on compounds first identified while screening for antibiotics.

Among the team is the University of Adelaide and GRDC Research Scholar Ryan McClean, who works at the coalface of this endeavour.

Pathways and inhibitors

Mr McClean explains the idea using glyphosate as the example. It inhibits the action of a plant enzyme.

That enzyme is part of a biochemical pathway that makes amino acids (the building blocks of all the proteins needed by the organism).

Glyphosate targets the pathway that makes the ‘aromatic’ amino acids (phenylalanine, tyrosine and tryptophan). Importantly, animals lack this pathway. Instead, they obtain aromatic amino acids from food. This is why a herbicide such as glyphosate has a reduced likelihood of being toxic to animals and humans but is toxic to plants.

“However, unlike animals and humans, bacteria possess these enzymes,” Mr McClean says. “What’s more, inhibitors to the bacterial enzyme counterparts have been explored as a way to make new antibiotics.

What we are doing is taking those candidates that failed as antibiotics and asking the question: can they work to inhibit the plant counterpart of the targeted enzyme and, therefore, function as a new herbicide?

New herbicide target

In testing this approach, the team targeted an enzyme that lies upstream in the same pathway targeted by glyphosate. The enzyme is called DHQS (dehydroquinate synthase).

Inhibitors of DHQS were previously developed and tested as antibiotics. Of particular interest were inhibitors that successfully target DHQS but failed to progress out of the lab as an antibiotic.
They are unable, for example, to enter the bacterial cell to get at the enzyme.

“We want compounds that failed as antibiotics – but not as inhibitors of the enzyme – so that we reduce the risk of off-target activity,” Mr McClean says.

He then crystallised DHQS sourced from the plant Arabidopsis. In partnership with Dr Santosh Panjikar at the Australian Synchrotron, they solved the enzyme’s three-dimensional structure. Next, it was compared to the solved 3D structure of the bacterial DHQS.

Computational methods were then used to understand how the inhibitor binds to DHQS at the atomic scale.

“Once we understand how the inhibitor interacts with DHQS, we can design modifications to the inhibitor that strengthen its potency as a herbicide,” Mr McClean says.

Working with the team’s chemist, Dr Andrew Barrow, inhibitor analogues were rationally designed, synthesised and retested by Mr McClean.

New pipeline

So far, about 40 analogues of the starting inhibitor have been processed.

Several have been identified that are more potent than the starting inhibitor ‘scaffold’. As such, a viable way to generate new herbicide candidates has been established.

But that is not the end of the development pipeline. Dr Soares da Costa notes that another phase of testing is needed.

“Ultimately, we can take the development work only so far,” says Dr Soares da Costa, who supervises Mr McClean.

“To get the herbicides to growers will entail collaborating with herbicide manufacturers to sort out costly hurdles such as formulation, toxicology and registration.”

Mr McClean says he is keen to take the development work as far as he possibly can in the year left on his scholarship and then remain working in the agricultural space.

Part of the reason is that the GRDC scholarship made it possible to interact directly with the beneficiaries of the research work – the grain growers – which is an unusual experience for students.

“For example, I was able to take questions directly from growers as a result of participating in a GRDC Research Update,” he says.

The [growers] opened up a new perspective on the power of research to make positive impacts to farm sustainability and productivity; and that has all sorts of downstream benefits to people and the environment.

Funding for this research program has also been provided by the Australian Research Council through a Discovery Project (DP220101901) and Future Fellowship (FT230100203) awarded to Dr Tatiana Soares da Costa.

More information: Ryan McClean, ryan.mcclean@adelaide.edu.au

Resources: GRDC Update Paper (2025) – Re-purposing failed antibiotics in the pursuit of novel herbicides.