Pseudomonas aeruginosa is a common cause of bacterial infections in humans, particularly in healthcare settings. It is relatively resistant to many antibiotics.Credit: Kateryna Kon/ Shutterstock
In 1945, after winning a Nobel prize for his discovery of penicillin, Alexander Fleming warned that misuse of the drug could result in antibiotic resistance. Almost 75 years later, in 2019, the World Health Organization declared antimicrobial resistance (AMR) as a top-10 global public-health threat. In the same year, 1.27 million deaths were attributable to bacterial AMR1. By 2050, as many as 10 million people could die annually as a result of AMR, costing more than US$50 trillion (UK£41 trillion) worldwide if no action is taken2.
“This is a truly global challenge,” says Dave Powell, chief scientific officer at UK self-funded medical research organization, LifeArc. “Better treatments and diagnostics accessible to all will be vital.”
Resistance is a natural evolutionary process that has been exacerbated by misuse of antibiotics in both healthcare and agriculture, as well as poor waste management and environmental transmission, increasing levels of resistant bacteria that persist after treatment. For a time, the biopharma industry remained ahead of the issue by creating a steady influx of new antibiotics — between 1940 and 1962, there were more than 20 new classes introduced to the market3,4.
More recently, there has been an antibiotic-development lull: only a small fraction of the antibiotics approved since the 1980s represent new compound classes, with most derived from already known chemical structures5. The availability of generic — or unbranded — medicines has made development less viable, so the evolution of antibiotic-resistant bacteria is now outpacing the discovery of new antibiotics. The slowdown has been driven by several challenges, including funding and development issues. Antibiotics have high failure rates in development: only one in 15 preclinical candidates in existing classes will reach patients, and the figure is just one in 30 for new classes.
To help tackle this problem, the UK government established an AMR strategy in 2013, which led to a 2019-2024 national action plan. A part of that plan is PACE: a UK£30 million initiative from innovation and research organizations LifeArc, Innovate UK and Medicines Discovery Catapult. PACE aims to strengthen pipelines of tests and treatments by removing barriers such as financial viability and skills gaps, and by supporting the early AMR research and development (R&D) ecosystem with both funding and advice for innovators.
The AMR challenge
Most current antibiotics are off patent and can be manufactured and sold outside of their originator company. This increased competition pushes drug prices down, so payers globally expect to pay less for antibiotics — a problem for drug companies who need appropriate funding to cover the high costs of development.
Other approaches to tackling AMR have included developing antibiotics of last resort — only used when all others fail. Limiting the uptake of new antibiotics helps to slow resistance, but this creates reduced financial returns that are less attractive to investors. The knock-on effect is a reduction in the number of companies and experts in the area, creating a skills gap.
The PACE programme will give researchers in academia and small and medium-sized businesses access to funding opportunities alongside advice, expertise, and support to increase the number and quality of early-phase antimicrobial and diagnostic R&D projects.
“Our initiative will deploy significant money to an under-invested sector,” says Chris Molloy, chief executive officer at Medicines Discovery Catapult, an independent, not-for-profit organization established by Innovate UK to reshape drug discovery. “It will also provide wrap-around support to inventors and innovators to put together R&D plans, creating networks of people and improving access to technologies.”
“We have a fragmented AMR R&D ecosystem,” says Richard Hebdon, director for health and life sciences at Innovate UK, the United Kingdom’s national innovation agency. “PACE’s mission is to look at areas of market failure and de-risk innovation for industry by strengthening pipelines and removing the development barriers.”
Antimicrobial clinical efficacy
Many of the older antibiotics are broad spectrum but are losing their efficacy as resistance rises. PACE is taking a leaf out of the precision-medicine playbook by focusing on the development of both precision antibiotics and rapid diagnostics, where clinicians can select the antibiotic that has the best chance to clear the specific infection.
“We need a precision medicine approach to treat bacterial infections, and to develop tools that will tell us which infection it is, and which antibiotics will be the appropriate ones to use,” says Hebdon.
PACE will start by understanding the priorities for new medicines and diagnostics development towards tackling AMR. The initiative will create target profiles of drugs and diagnostics needed most urgently, seek proposals to address those needs and build networks and collaborations.
“There will be multiple waves. The first call will be for antibacterial assets targeting the most threatening multidrug-resistant pathogens,” says Molloy. “Subsequent waves will include calls for diagnostics and potentially drugs that target fungal pathogens. PACE will also look to engage additional funders and agencies.”
PACE’s first funding call is open, with up to UK£10 million available for innovators progressing new antimicrobials for the most-threatening microbes and resistance mechanisms. The funding will support 8–12 projects with up to UK£1 million for each.
“It will begin as a five-year programme, but we want to build something bigger that can take on a life of its own,” says Hebdon. “Our goal by five years will be to move the United Kingdom to a more efficient AMR R&D ecosystem.”
Pushing and pulling towards a new pipeline
Resistance to antibiotics and other antimicrobials isn’t going away, so part of the solution to the AMR crisis will be to develop and trial plenty of new candidates.
“Our ambition is to catch up with where we have allowed evolution to overtake us. This will be ongoing,” says Molloy.
Because of the industry slowdown, this requires both ‘pull’ approaches that meet the industry’s need for income, and ‘push’ approaches that encourage the development of new technologies and projects. Pull approaches include subscription payment models, such as that first piloted by National Institute for Health and Care Excellence and National Health Service England in 2022.
“Subscription models in some countries provide drug companies with the confidence of being reimbursed. Such programmes are essential until normalized commercial conditions are once again in place,” says Powell.
Push initiatives that fund and support promising R&D have provided scientifically diverse early-development pipeline candidates, but there is still a gap in supporting R&D in the preclinical space that PACE aims to fill.
“We need to get investors and the industry excited about new treatments and diagnostics,” says Hebdon. “PACE is a push initiative within a wider landscape that can both strengthen the pipeline and increase confidence in tackling AMR long-term.”