Tony Velkov and Jian Li share the kind of geeky science story that would work perfectly as a Hollywood script.
On quiet weekends at the Monash University science labs 20 years ago, the pair discovered they were the only ones crazy — or obsessed — enough to be working on their projects while everyone else was at home enjoying a few days off.
Then, when Velkov and Li realised they shared not only a work ethic but a passion for researching bacteria, their personal and professional friendship was sealed.
"We were the only guys working Saturday and Sunday and we kept running into each other," Velkov remembers. "From then on it's just been fun, you know, we sit around for hours talking and brainstorming. We have been a really good team."
Over the past 12 years, the two scientists have been developing a new antibiotic that recently began phase 1 clinical trials in the US.
Their intravenous drug targets deadly "superbugs" that are difficult to treat but can run rampant in hospital settings, causing pneumonia, blood infections, urinary tract infections, peritonitis and meningitis.
This promising new drug, with the uninspiring name QPX9003, has placed the pair on the cusp of achieving something that hasn't been done for decades.
No new antibiotics in this class — polymyxins, which target hard-to-kill "gram-negative" bacteria — have been approved since the 1950s. In March, their research was published in the journal Nature.
For anyone researching bacteria and antibiotics, getting a new drug to a clinical trial is the holy grail. But it's been a lonely, gruelling process for Velkov and Li, who have at times stumped up their own cash to keep the research going.
"It can be a thankless job," Velkov says matter-of-factly.
But why?
Without new antibiotics, the world is on track to re-enter the medical dark ages by 2050, when a simple cut could kill 10 million people a year.
So why are they so hard to find?
A hidden crisis
For most of us, antibiotics don't feel like a big deal. At the slightest sign of a cough or a rash many GPs will dash off a prescription for antibiotics and we're all "popping them like Tic Tacs", Velkov says.
While our medical and pharmaceutical resources have been (importantly) absorbed in solving the COVID-19 pandemic, the problem of antibiotic resistance is continuing to gain pace.
Each year in Australia more than 55,000 people are diagnosed with sepsis — when an uncontrollable bacterial infection triggers inflammation throughout the body. If it can't be managed, sepsis can lead to organ failure. And effective antibiotics are a key component of treatment.
About 8,500 Australians die from sepsis every year. It's a huge figure, far above the annual road toll and higher than deaths from specific cancers, and it has a huge economic impact too: antibiotic resistance costs the economy about $700 million a year.
Many scientists, Velkov included, argue the threat ahead from bacteria is equally as serious as that posed by the SARS-CoV-2 virus.
So why is money to invest in antibiotic research so hard to come by?
A medical miracle
Just 100 years ago, as many as one in three deaths was caused by bacterial infections developing from injuries that would barely raise an eyebrow these days.
Back then, if bacteria entered a cut or infection took hold after surgery, the wounds were doused in bromide — hugely painful and deadly to healthy cells too — or treated with bloodletting and leeches.
Then, in September 1928, British scientist Alexander Fleming returned from his summer holiday to find one of the petri dishes of Staphylococcus bacteria in his lab had a big blob of mould growing in the middle of it. Yet the area around the mould was free of bacteria and Fleming wanted to know why.
The answer led to the development of the first antibiotic – penicillin – and by the mid-1940s it had become widely available. Medical care was transformed.
It used to take a particular bacterial strain a few decades to evolve to overcome the antibiotic designed to kill it. But these days, says Dr Maytham Hussein, a researcher in alternatives to antibiotics from the University of Melbourne, it takes some bacteria only two or three years to learn to resist a particular antibiotic. Some bacteria become resistant before clinical trials have even been completed.
The problem is that bacteria reproduce faster than just about anything on the planet, some strains doubling their numbers in under five minutes. As the human population increases (giving bacteria more places to multiply) and more and more of these people use antibiotics to get over their infections or keep them safe after surgery — or agriculture uses antibiotics to keep infection in animals at bay — bacteria have many more opportunities to become resistant. And as this process speeds up, the probability that bacteria will find a way to overcome antibiotics increases. The result is that our stash of usable antibiotics is dwindling.
Those golden staph outbreaks we hear of invading hospitals provide a glimpse of what a post-antibiotic world could look like. Or worse still, a return to the bubonic plague pandemic that devastated Europe, Asia and North Africa in the 1300s.
Has the post-antibiotic era already arrived?
There are plenty of medical experts who believe the post-antibiotic era is already here and COVID has supercharged the need to address the problem.
Ventilators that are relied on to treat many of COVID's sickest patients in ICU also place those patients at increased risk of bacterial infection. Before COVID, ventilator-associated pneumonia (VaP) was already a widely noted medical phenomenon, affecting between 5 and 40 per cent of intubated patients.
Of those diagnosed with VAP, up to 10 per cent die from a bacterial infection, not the illness that brought them to ICU in the first place.
But it's not just desperately ill COVID patients who are vulnerable. Without effective antibiotics, the healthcare we take for granted – from giving birth and knee replacements to heart bypass operations and surgery for cancer – would carry the risk, once again, of exposing the patient to a life-threatening infection.
"This is the slow pandemic," says Professor Matt Cooper from the Institute of Molecular Bioscience at the University of Queensland.
"Politicians and funding bodies [respond to] acute crises, and don't get me wrong COVID is a serious disease, but with antibiotic resistance we are like a frog, slowly boiling on a stove."
So where are the new antibiotics coming from?
With so much at stake, you might think that pharmaceutical companies would be tripping over themselves to invest in the next great antibiotic and back the next Alexander Fleming or Tony Velkov.
But there's a problem.
The speed with which bacteria challenge and overcome new antibiotics isn't just a scientific problem. It is also an economic one: pharmaceutical companies don't have time to make a profit.
Of the antibiotics that do make it to market, most are lucky to have a 10-year life span before bacteria become resistant, Velkov says.
And when it costs up to $1 billion to develop a marketable drug, a decade isn't enough time for pharmaceutical companies to get their money back and deliver a profit. Tweaking the drugs to give them longevity isn't much help because when global patent laws run out, typically after about 25 years, the generic manufacturers move in.
"There's not much money in antibiotics," Velkov says. "For pharmaceutical companies, it's literally like a charity, a pro-bono activity for them, and they are not investing."
Cooper agrees: "It is really simple, [the problem is] money, and everyone is leaving the field because it's so depressing. It's really, really hard to stay motivated."
Instead, big pharma is investing in drugs for conditions like rheumatoid arthritis, melanoma and blood clots — which made up three of the top five biggest-selling drugs of 2021. Pfizer's COVID vaccine came in at number one. Moderna at number three.
'A thankless job'
Velkov's close relationship with Li has sustained them both through the long years of research with little but their own scientific curiosity to keep them going.
But Velkov says he also found motivation from something deeper: the idea that his work could make a difference.
"He's a very good friend of mine and we work really well together," Valkov says of Li. "Many professions become about reputation, ego and achievement, whereas we don't really care what other people think of us. If our work can actually change the way people live, or help them live better, then our work means something. That's what science and medicine is about. When you lose touch with that central philosophy, you're in trouble."
Nevertheless, he admits matter-of-factly that a career devoted to bacteria and developing antibiotics can be "a thankless job".
The two scientists years ago gave up expecting R&D funding from Australia. Of course, they had support from the university sector and then tipped in more of their own cash at critical moments, but the big investment required to make their new drug a reality came from overseas.
"It's just all about investment and development, that's all it is," says Velkov of the difficulty finding new antibiotics. "We can fix this problem [of antimicrobial resistance] but governments need to prioritise it. They can't rely on drug companies and they can't rely on Jian Li and myself mucking around in the lab on our days off. We are just two blokes trying to scrounge together materials to build something."
With pharmaceutical companies wary of the financial risk of significant investment, a number of government-backed funding bodies have been set up in other countries to support drug development.
Velkov and Li received two $US4.5 million donations from a US-government investment fund known as BARDA, the Biological Advanced Research and Development Authority, that enabled them to finish the research for their intravenous antibiotic.
He wishes the Australian government had similar investment capacity: "That's not even possible in Australia. We don't even have grants that size. Down Under, we just do things too small," he believes.
Even better, Velkov says, would be establishing a global alliance — in particular, partnering with China where significant research is underway — that can pool medical developments for the greater good.
It's an idea Cooper has tried several times, currently as a not-for-profit project that screens compounds for antimicrobial activity with a goal to help researchers discover new compounds that are effective against drug-resistant infections.
'Really, really hard'
Funding difficulties are only one part of the problem.
"I want to stress that this is tough," says Cooper, pointing out that the technical difficulties of finding and developing new antibiotics are real.
Researchers have scoured nature to find new antibiotics from coral reefs, soil and even bat dung but "there hasn't been much success", says Cooper, who is preparing to publish his findings outlining the key problems facing the development of antibiotics and flags key areas of promising research.
Notwithstanding disappointing results from searching the environment for new sources of antibiotics, the importance of protecting nature remains the key, says Velkov.
"Most of our medicines are natural products and we haven't come close to tapping into all of these natural resources," he says.
Solutions to the superbug
Four avenues are being explored to combat the rise of the superbug.
One is to continue to push the message that existing antibiotics must be used sparingly and carefully to minimise the potential for bacteria to become immune.
Another is reviving antibiotics that were previously passed over because something better came along. Returning to these discoveries saves research and development money, making them a more attractive investment.
Scientists are also searching for ways to support or boost the effectiveness of existing antibiotics by using other drugs and therapies, known as "potentiators".
Maytham Hussein's work looks at the effect of cannabinoids, which if taken in tablet form can boost the performance of antibiotics.
Cooper is undertaking associated research that uses peptides as potentiators.
Then there is the phage therapies, a branch of medical science that harnesses viruses to attack and kill bacteria.
Finally, there is immune modulation known as "inflabiotics", which uses similar strategies to the immune therapies being used successfully in cancer treatment.
"These get the ancient part of our immune system, our innate immunity, to stop making 'bad' inflammation and instead clear the infection with 'good' inflammation," Cooper says.
He anticipates this therapy would face fewer issues with drug resistance because it targets the immune system, not the bug itself. "If it is viable, it could be broadly applied," he says.
Is time running out?
Cooper is confident more antibiotics can be found or alternative therapies discovered. But he fears the struggle for funding has made bacterial research a disappearing field.
He calculates that fewer than 1,400 researchers — experts in bacteria and antibiotics — remain working around the world. Of those, he estimates most are in their 50s and 60s and due to retire in the next decade.
"At some stage, not only will there be no money for research but all those experts will leave the field," he says. "Ninety years of knowledge about how to discover and develop antibiotics, these miracle drugs that have saved more lives than any other drug, will be gone."
