‘We’ve reached peak antibiotics’

Superbugs are one of the greatest threats to human health, and Kiwi researchers are using several pioneering methods to find new ways to help.

When antibiotics entered widespread use 200 years ago, they changed our lives, giving us a weapon against common bacterial infections that can kill.

Since then, some bacteria have developed resistance to certain antibiotics, leading to the rise of superbugs, which are becoming a major problem in New Zealand hospitals. 

A 2016 report by the Institute of Environmental Science and Research (ESR) for the Ministry of Health found New Zealand was one of the highest users of antibiotics in the developed world. 

Many antibiotics can no longer be used, and on the horizon is the possibility that infections once thought conquered may kill again. 

Contributing to the problem is the historical misuse of antibiotics: prescriptions for viruses, people failing to complete their courses of medication (thereby allowing bacteria to evolve to resist the antibiotics), their use in food and meat production, and antibacterial soaps in home and industrial cleaning products, which go straight into our waterways.

The World Health Organisation recently described humanity as being in “a race against time” to develop antibiotics against multi-drug resistant superbugs. According to one estimate, annual deaths from superbugs will reach 10 million by 2050.

But despite the threat of widespread resistance, research into new antibiotics has been declining since a golden age of discovery in the 1940s-1960s. However, several New Zealand scientists are searching for answers. 

We simply need more money for research, says Dr Siouxsie Wiles, who Newsroom featured in May when she and CureKids launched a crowd-funding effort to pay for her testing of 1000 soil and fungi samples for their potential to kill superbugs. So far, the effort has raised 111 per cent of her $250,000 goal: nearly $280,000.

That’s a sentiment repeated by Massey University microbiologist and senior lecturer Dr Heather Hendrickson, who has been working in the field for 17 years.

“I would love to see more interest from funding agencies in this sort of work,” she says. 

An age where humans die of common infections isn’t far off. “We’ve reached peak antibiotics.”

Hendrickson investigates a range of issues, including how bacteria evolve and the discovery of viruses which infect them, called bacteriophages. 

“These are the ancient enemies of bacteria and they have huge potential as a tool to kill bacteria,” she says. “But we have barely scratched the surface of their diversity; they are still largely unknown.”

One of the processes she studies is horizontal gene transfer, where even distantly-related bacteria exchange DNA, including genes that are resistant to antibiotics. It can also result in new pathogens.

She says the work is of “critical importance”. New Zealand is seeing increased instances of antibiotic resistance in many of the same pathogens noted by the World Health Organisation. 

She was recently part of the Royal Society of New Zealand review on the topic, which collected data that suggested New Zealand is witnessing increases in methicillin-resistant Staphylococcus aureus (a common cause of skin infections, sinusitis, and food poisoning); further resistances in some gut bacteria, like E. coli; and also those that cause sexually transmitted infections, like Neisseria gonnoroheae, responsible for gonorrhea.

With one of the issues in antibiotic resistance the use of the bacteria-killers in animal feed, Hendrickson says we need to start demanding meat be labelled with whether or not antibiotics are used during production. 

“This is a step that is being considered in legislation elsewhere and I think it would make consumers more aware of the actual costs of the cheap meat that they are eating.”

Consumers can help by not buying antibacterial soaps, by not using antibiotics unnecessarily (e.g. for a virus). “We can all play a part in ensuring that antibiotics last for as long as possible.”

As for a solution, she says she’s interested in scientific projects that involve looking for new antibiotics. “I also think we need to consider approaches like phage therapy and phage therapeutics, where we use the natural enemies of phages and their products to fight bacterial infections where possible.” 

At Victoria University of Wellington’s School of Biological Sciences, senior lecturer Jeremy Owen and associate professor and biotechnology programme director David Ackerley are searching for new antibiotics from bacteria that live in soil and other complex environments. 

They are at the forefront of this particular type of synthetic biology approach to discovering new drugs.

“If we cannot find effective new antibiotics soon, we may be faced with a return to the 1920s pre-antibiotic era, where people routinely died of the most mundane things, like a scratch from a rose thorn while gardening,” David Ackerley says.

“The good news is, we have learned a lot over the past 70 years about how to better use antibiotics to slow the development of resistant bacteria. The bad news is that in that time we have burned our way through nearly all of the antibiotics discovered to date. We are trying to refill our pharmacies with new antibiotic options.”

The majority of antibiotics in use today were discovered by growing bacteria isolated from different soils around the globe, testing the different molecules they naturally secrete. 

The pair say this was a highly productive approach between the 1940s and 1960s, but researchers have struggled to find anything new since. 

“The same sets of molecules just kept cropping up time and time again,” Ackerley says. “In recent times we have realised that only a very small proportion of soil bacteria – under 1 percent – can be grown effectively outside of their natural environment. It is a certainty that the remaining 99 percent produce some very effective antibiotics that we have previously been unable to access.”

Because most soil bacteria can’t be grown in a lab, the team are going straight to the bacteria’s DNA, purified from the soil. They’ve developed several different strategies to ‘fish out’ clusters of gene that encode antibiotic-synthesising cellular machinery. 

“These genes effectively act as blueprints that tell a cell how to make one particular antibiotic,” he says. “Taking advantage of the fact that bacteria are so good at swapping bits of DNA, we and others have shown that you can employ ‘synthetic biology’ approaches to transfer these blueprints to a new host – a bacterium that we can grow in the lab – and a surprising amount of the time it will gain the ability to produce a new antibiotic.

“Luckily for us, most antibiotic gene clusters not only encode the assembly line needed to make an antibiotic, but also a means for defending the host cell against any toxic effects, so the new bacterial host is usually immune to the new drug it is making.”

He says big pharma companies seem to be increasingly interested in this space, which bodes well for downstream development of promising new drug candidates.

Four questions for Victoria University of Wellington's David Ackerley

Are we doing enough to tackle this global problem?

No. Not yet. Until very recently there has been little incentive for large pharmaceutical companies to develop new alternatives to current antibiotics, as any new antibiotics to hit the clinic will likely be reserved to treat only the cases where the current frontline drugs fail. 

Because antibiotics work so well in curing disease then patients don’t need to keep taking them for years on end (in fact, good clinical practice will do what it can to discourage unnecessary use). All of this reduces profit margins for the pharmaceutical companies. 

However, there are starting to be “prize-type” financial incentives implemented by governments to encourage discovery, moreover the fact is the situation is starting to get really dire, so the market for new antibiotics that are effective against drug-resistant superbugs is unfortunately growing all the time.

How is your work funded?

Our main source of funding at present is a $1.2m grant from the Health Research Council of NZ, specifically for discovery of new antibiotics. But one of our key methods for finding promising gene clusters came out of an unrelated ‘blue skies’ Marsden project, which really emphasises the importance of funding basic research to enable unexpected discoveries. 

We have also received supporting funding from the Maurice Wilkins Centre for Molecular Biodiscovery and the Cancer Society of NZ, to try and find promising anti-cancer drugs in a similar manner.

Coming back to the basic discovery level, it’s really hard to get funding for a project that wants to search for new drugs – the fight for scientific research funding is so competitive that grant review panels tend to strongly favour projects with a logical and clear progression of goals and a high likelihood of success. 

They usually don’t like projects where the first aim is to find new compounds, as all the remaining aims will be 100 percent dependent on the first one, and if that is not successful the whole project falls over. The phrase commonly used to dismiss such projects is “that’s just a fishing expedition”, and to get past that criticism you usually have to convince the panel your methods are incredibly new and exciting, and have a high likelihood of success. 

Otherwise, you are faced with the chicken-and-egg scenario that you can’t get the funding without having already found the new drug candidates, after which you no longer need the funding for the discovery work.

Given the severity of the problem, it does seem that having a few decent-sized grants reserved to specifically target discovery of new antibiotics might be warranted.

Who needs to make changes to ensure we are looking at ways to solve this issue?

At an academic or small company discovery level, government policy decisions can have a big impact on priority areas for funding. For drug development, governments can again play a key role in incentivising companies to develop new antibiotic drugs even if they will be reserved only to treat the most severe drug-resistant cases. 

Large philanthropic organisations like the Gates Foundation can also potentially help provide incentives in the form of prizes etc for new clinically-approved antibiotics that won’t have a large patient pool, so that companies have a way of recouping the many hundreds of millions of dollars of investment it takes to bring a new drug the whole way from discovery to large and very expensive clinical trials, and ultimately to market.

How far off is a “solution” to the problem of antibiotic resistance, and what might that look like? 

The preclinical and clinical trials needed to ensure new drugs are both safe and effective are not only super-expensive, they also consume large amounts of time. The problem is getting so severe that it is possible the next generation of antibiotics will be rushed through expedited trials in only a few years rather than the more usual decade or so – however, that kind of approach of course brings risks in that any side-effects or possible longer-term consequences of any approved drug will be less fully understood. 

At any rate, the good news is that there are new types of antibiotics starting to come through the pipelines again. But we are nevertheless going to be faced, at least for a while, with increasing numbers of infectious diseases that are not safely treatable if they are even treatable at all.

- newsroom.