Young Frenchman Dr Thierry Izoré, a Monash University research fellow and structural biologist, uses the analogy of a car factory’s assembly line to help explain his complex work with microscopic bacteria, which he hopes may be able to build lifesaving hospital antibiotics.
The bug he’s interested in is what he calls a “hot bug” – Thermobifida fusca, which grows at high temperatures (55-60 degrees Celsius). In the wild it can be found in rotting compost, manure or rotting hay. A hot, smelly little bug. And a tricky one to work with, as it turns out.
Dr Izoré works in the Biomedicine Discovery Institute’s Cryle Lab at Monash, which focuses on making new antibiotics to treat acute bacterial infections. Most antibiotics are made from compounds found in nature; the lab’s job is to re-engineer the enzyme structures that produce them and, in the process, see how they work.
That’s where the car factory analogy comes in. He makes it sound easy, but it’s highly complex lab work.
Essentially, what scientists of this kind do is look at very small things to see what they do, then try and change them to make them do something different, in conjunction with other compounds. In this case, the tiny organism Thermobifida fusca is being used to figure out how to make non-ribosomal peptide synthetase (NPRS), which in turn can be used to make crucial last-line antibiotics.
NPRS “machineries” can be seen as “an assembly line”, he says.
“Antibiotics are made of building blocks, and each building block is fused to the other one in the assembly line. Like in a car assembly line, the first station does, for example, the base of the car, then it moves on to the second station, and so on.
“It’s exactly the same in NPRS,” he says. “Each module is responsible for the incorporation of one building block. If we manage to incorporate a new building block it will produce a new antibiotic, we think.
“We need to understand in the assembly line how we can modify a module so that it stays active and at the same time incorporates the new building block in the final compound. But we don’t know how they interact with each other. When we remove, exchange or alter a module within the assembly line, the machinery stops working. We don’t know why.”
The research has this year received a $55,000 Contributing to Australian Scholarship and Science Foundation (CASS) grant.
The project is called “Studying hot bugs to make good drugs”. The aim is to produce last-resort hospital antibiotics to counter the rising tide of human resistance – but Dr Izoré knows this may not even be seen during his career. It’s estimated that by 2050, there’ll be 10 million deaths globally a year due to antibiotic resistance.
“We dare to dream that our work might become medicine,” he says. “But that is very far away, although I hope not, because we need new compounds sooner than that. We want to be the first to do it.”
This year, the hard structural biology work continues.
A bug of stability
The main reason the “hot bug” is Dr Izoré’s favourite is because it’s strong. Its proteins and enzymes are considered highly stable. Most bacterias grow at room temperature, or around 20 degrees Celsius. They don’t like being modified in the lab, and their proteins are unstable.
Different species of bacteria need to fight each other to gain resources. They do this by producing antibiotics that kill the other species. For this reason, most of the antibiotic-producing bacteria live at these low temperatures.
Watch episode 10 of A Different Lens: Beating the Superbug
The bug in question is hotter than that, and doesn’t mind being manipulated to have enzymes extracted, yet it still produces NRPS enzymes and antibiotics.
“It gets the best of the two worlds for us,” he says. “It produces NRPS enzymes, and because it’s a thermophile or ‘hot’ bug, the NRPS enzymes are very stable.”
But there’s a catch. The hot bug grows painfully slowly. Strong, but slow. So, Dr Izoré and the Cryle Lab team used E.coli, the common bug that lives in the intestines of humans and animals, to boost the process. DNA from the hot bug is extracted and given to the E.coli, which grows quickly. Initial tests show the process is working.
“Everything is ready; we just have to do the assembly successfully, then check that it’s functioning. Then we can start a structural study, and hopefully it gives us what we want and we’ll be able to see for the first time how a completed assembly line is.
“Then,” he says, “we can modify it and produce a new compound.”