An enlightening read....Following years of COVID-19 and...

An enlightening read....

Following years of COVID-19 and countless films and TV series about plagues and killer fungi, it’s fair to say that the world is now well attuned to the threat of a superbug apocalypse.

Disruptive pandemic aside, it has been a long time since humans reckoned with something as horrific as the Black Plague, which had mortality in the order of 30-50% – compared to COVID, which at its peak had a mortality rate of up to 3% – and condemned an estimated 75-200 million in Europe to a gruesome death.

“Many of us have been living in an era where infectious disease was not a real threat,” says US-based Linnaeus Biosciences chief scientific officer Marc Sharp.

“The COVID-19 pandemic has hopefully been a wake-up call. It emphasises that infectious disease can be devastating, both as a human toll and an economic and social one.”

What’s at stake?

We owe our modern way of life to antibiotics.

Until the advent of penicillin in the early 20th century, there was no such thing as routine surgery – poisonous sepsis was an ever-present risk.

In the many happy and prosperous years since, billions of people and animals have avoided a painful death from bacterial infection.

Intravenous, preventative antibiotics have de-risked the highly complex operations we take for granted these days to head off mortality from cancer and circulatory diseases.

Antibiotics have also kept dangerous bacteria at bay, so that UTIs, acne and other ‘minor’ infections stay that way.

But this may soon change – for decades now, superbugs have been evolving on our watch.

Antimicrobial resistance (AMR) is the problem of bacteria and microbes that have figured out how to defy antibiotics – our only existing line of defence.

In the last few decades, overuse and misuse of this vital frontline treatment in agriculture and medicine have allowed targeted bacteria to evolve into superbugs, against which many of the antibiotics we have are powerless.

Just like machine learning, which learns from our data, bacteria learn biologically from the antibiotics in our waterways, in our systems because of overzealous prescription, and in our food, thanks to their use in industrial farming, where they are used as preventatives against disease in cramped quarters.

“Part of the problem is that the environment is flooded with them, and part of it is that we're coming up against new bacteria to fight,” says Recce Pharmaceuticals Ltd (ASX:RCE, OTC:RECEF) CEO James Graham. “It’s an evolution taking place – to survive, things mutate and evolve.

“Bacteria have a very intelligent protection mechanism. It’s a hypercellular mutation that takes place to allow the bacteria to innovate, adapt, overcome and be otherwise ahead of traditional antibiotics.”

An evolutionary battle

“It’s helpful to look at the AMR problem from an evolutionary perspective,” says Sharp. “Most of the antibiotics on the market are either natural products or derivatives of natural products.

“They are essentially chemical weapons that bacteria and other organisms have been making and using to get a competitive edge for about 3 billion years.

“Bacteria are very good at evolving ways to avoid or tolerate antibiotics, and they have been doing it for a long time. Plus, when they luck into a way to avoid an antibiotic, they hit the evolutionary jackpot because they gain the ability to live in an environment none of their competitors can tolerate.

“AMR is not an impending event, it’s something that has been happening forever, and is happening all the time.

“Our only rational response is to assume every drug will eventually become ineffective and constantly search for new ones.”

“Antibiotics have been presented as much like a key in a lock – you've got the bacteria, and you've got the antibiotic,” says Graham. “Today, they may come together and an ideal mechanism of action might take place.

“But tomorrow, having seen that attack work so effectively, the bacteria change and evolve a little bit so when that when the enemy comes along to try to attack them again, they’ve worked out a way to get around it.

“The bacteria have mutated – they always have and always will – but antibiotics are just not keeping up.

“What it requires is a new class of drug that's able to work and keep on working with repeated use to overcome that simple problem of antibiotic resistance.”

The scale of the problem

AMR is a global problem – the World Health Organization recently noted an estimated 4.95 million deaths attributable to antibiotic-resistant bacteria in 2019.

It disproportionately affects low- and middle-income countries because it is harder for them to access the latest and most effective antibiotics, and resistance is higher.

That said, the CDC reported nearly 3 million antibiotic-resistant infections in the US in 2017, with more than 35,000 deaths. In Australia alone, superbugs are thought to kill 5,000 people per year – and these numbers aren’t going to shrink.

“It is a major unmet medical need – around US$130,000 per patient on a treatment basis,” says Graham.

“In high-income countries, where people have better access to the latest drugs, antibiotics may be over-prescribed, and patients may not complete courses, again leading to selection for resistance,” says Sharp.

“Resistance is the result of random mutations, so it can arise anywhere and, with a globally connected world, a resistance mechanism can spread everywhere. Just look at the last three years and how a mutant virus that was never a threat to humans shut down the world.

“Humans have been making and using antibiotics for less than 100 years, and a lot of the easy sources of new compounds and targets have been exhausted.

“We have the brains to come up with new ideas, but bacteria have the numbers to try lots of different responses.

“Unfortunately, often when a new resistance mechanism evolves it can render entire classes of antibiotics ineffective.

“Plus, bacteria are good at swapping genes around, so resistance mechanisms can move between bacteria, making the problem even worse.”

The silent pandemic

When antibiotics – which have underwritten our way of life for the last 100 years – are no longer effective, mundane medical procedures will become almost impossibly risky.

A common surgery like a caesarean section or a tonsillectomy, or an annoying but simple health problem like a UTI, could quickly become a death sentence.

“If a resistant pathogen took hold in hospital settings it would make surgery of any kind almost impossible, due to the risk of untreatable infections, and would make virtually any other invasive care exceedingly dangerous,” says Sharp.

This is borne out by a new report released by CSIRO and the Australian Academy of Technological Sciences and Engineering warns that if we continue to ignore the growing threat of AMR, deaths from simple infections will rapidly increase.

“The first thing that we see happening is that we need to change our treatment guidelines,” Branwyn Morgan, who leads the CSIRO’s response to AMR, told the ABC.

“So, doctors, instead of prescribing one antibiotic first off, will know that because of high rates of resistance in a particular area or community, they actually have to start with another one.

“But essentially what will happen when all our antibiotics begin to fail, and in some cases they have, [is that] we won’t have anything left to treat infection.

“We can develop new antibiotics, and we are, but we do require a more holistic approach to AMR management.

“Microbes evolve very quickly and they’re designed to survive. Anything we throw at them over the long term is going to generate resistance mechanisms.”

Market realities and failures

Just like the other seemingly overwhelming problem the planet faces – climate change – the fight against AMR is compromised by market and incentive failures of industry.

The biggest returns come from drugs that will be taken for a long time by a lot of people, allowing pharmaceutical companies to cover the substantial costs of research, development and clinical trials.

By contrast, any new antibiotic would need to be used as sparingly as possible, as a last line of defence if other existing treatments fail – it would otherwise go the way of all the other antibiotics the superbugs have knocked out.

This means there is scant market incentive for pharmaceutical companies to pursue new antibiotics.

“To combat AMR, there will have to be a new paradigm for antibiotic development,” says Sharp.

“Some countries are looking at new programs, such as subscriptions that ensure certain levels of sales, but much more needs to be done are we are at risk of getting to the point where untreatable infections are common with no new drugs on the horizon.”

The landscape has changed since COVID-19, where it became clear that the population – indeed, pandemic – scale of the problem could deliver the economy of scale needed to ensure a pharmaceutical company had the payday it needed to fashion a solution.

Hope on the horizon

“We believe the solution requires a whole new mechanism of attack,” says Graham. “We need a new class of antibiotic to really adapt to the latest pathogens, or most ideally adapt to and overcome that hypocellular mutation beyond.”

Graham’s company, Recce Pharmaceuticals, is one of a handful working on such a solution.

Recce is fielding two primary drug candidates – RECCE 327 for bacterial infections and RECCE 529 for viral infections.

The company recognises the critical lack of innovation in the antibiotic drug development field and acknowledges that there is an urgent need to develop a new class of anti-infectives.

RECCE 327 is one of the first new classes of antibiotics in more than 30 years with a universal mechanism of action that allow its compounds to continuously kill bacteria and multi-drug resistant superbugs.

Graham says that the mechanism used by RECCE 327 ensures that bacteria will not be able to reckon with it.

In the past, clinicians would have to identify what type of bacteria is causing the infection, and what type of antibiotic it’s susceptible to – assuming it’s susceptible to any at all.

“At the patient’s admission stage, they instead just give you a cocktail of antibiotics in the hope that they'll manage to hit whatever that underlying bacteria is. It's absolute guesswork,” Graham says.

“We look to these brilliantly intelligent little species and ask: how do they survive? How do they get away with not being inhibited by the antibiotics?

“They do things like assuming a lipid outer layer or a goo so that antibiotics can't stick to them. They have internal efflux pumps, so that when an antibiotic seeks to come in, it is pumped straight back out.

“Then there is a hybrid of other mechanisms such as turning off cellular energetics or removing their active or stagnant state forms.”

Recce’s candidate has been designed not to succumb to those methods of resistance.

The small molecule compound can penetrate the bacterial cell surface. “And the efflux pumps can pump away as much as they like once we are in, we work to shut down the ATP synthesis which is also known as the beating heart of the bacteria,” Graham says.

“It's basic cell energetics and we shut it down irreversibly. We will have worked by way of our desired kill characteristic faster than they're able to excrete us.”

In the race to get ahead of the so-called silent pandemic, this new generation of anti-infectives offers a glimmer of hope we haven’t had for decades. /end/