Diana Spencer speaks to Christopher Reid, Professor of Biological and Biomedical Sciences at Bryant University, in Rhode Island, US, to understand the issue of antimicrobial resistance, why there are so few new antibiotics in development and where the drug discovery opportunities can be found.
The scale of the crisis
In July 2023, a report by University of Queensland (UQ) researchers warned a global crisis of antibiotic resistance is inevitable, despite promising developments in new antibiotics.
It’s a bleak outlook. The World Health Organization (WHO) estimates 700,000 deaths each year are attributable to antimicrobial resistance (AMR) globally. WHO estimates that this will grow to 10 million per year by 2050 if the current trend is not suppressed, and while this is a global issue, low- and middle-income countries represent the largest hotspots of resistance.
Reid explains why the situation is so critical: “The spread of AMR is outpacing most counter measures and we have an increasingly limited choice to treat infections. This has a huge cost to the health care system. While the dwindling number of antibiotics without resistance issues is a significant and growing problem with bacterial infections, the problem is even greater with fungal infections given the smaller number of clinically useful antifungal agents and the dearth of new antifungal development.
“The implications for not addressing this epidemic are the loss of effective antibiotic treatments where previously-treatable infections become costly, serious, long-term medical ordeals that could ultimately prove lethal.”
The link with rising air pollution
A new study has linked antibiotic resistance with rising air pollution. The researchers looked at air particulate matter in 19 cities in eight of the climate zones around the world and detected antimicrobial resistant genes associated with the particulate matter.
This is an interesting finding, but many questions remain regarding the significance of the link between the two factors. “While the authors show a correlation between air particulate matter and antimicrobial resistant infections, the data does not currently support a causal relationship,” says Reid.
“Significant work remains to be done to connect the presence of antimicrobial resistance genes present on air particulate and the rise of antimicrobial resistance, in particular, the long-term inhalation of particulate matter associated genetic material and how it can lead to the development of clinically relevant lethal resistance. Also, the fate and consequences of inhalable antimicrobial resistance genes in interactions with microbiomes in healthy and diseased human airways is not currently known.”
Challenges in creating new antibiotics
The Centre for Superbug Solutions at UQ’s Institute for Molecular Bioscience revealed that 62 new antibiotics are in development, with 34 of those based on structures not previously used as an antibiotic. However, this pipeline is still much thinner than those for other diseases, like cancer.
So why aren’t there more antibiotics in clinical development? Low market incentives and a lack of patients for clinical trials are two of the hurdles that companies must overcome. Reid expands: “Only about one in five infectious disease drugs that reach the initial phase of human testing will receive approval from the FDA. Developing antibiotics to treat highly resistant infections is particularly challenging as only a small number of patients contract these infections and meet the requirements to participate in traditional clinical trials. Finally, the current market incentives for investing in antibiotic development deter investment in this area as creeping resistance issues will shorten patent lifetimes.”
What can governments do? “There is need to continue to incentivise the development of new treatments through “push-pull” incentives such as those targeted at lowering the cost of developing new antimicrobial agents (tax credits, grants, public-private partnerships, etc) and extending patent exclusivity among others. Additionally, continued funding of R&D efforts in basic and applied research that will enable future breakthroughs,” says Reid.
Many countries are beginning to realise the extent of the problem. In August 2023, the UK government announced up to £210 ($267) million of funding to partner with countries across Asia and Africa to tackle antimicrobial resistance (AMR), following a previous £39 ($48) million investment through the Global AMR Innovation Fund (GAMRIF) in May. However, it is clear more support is needed.
Opportunities for drug discovery
Reid points to the development of combination therapies, combining traditional antibiotics with a compound that inhibits the pathway that confers resistance, as having the potential to breathe new life into the existing antimicrobial arsenal. Recent antibiotic discovery has included non-traditional candidates for antimicrobial chemotherapy, such as microbiome modulating agents, bacteriophage treatments, therapeutic antibodies, and immuno-modulating agents.
“I see multiple opportunities for drug developers to create new products,” he says. “As our knowledge of the host-pathogen and pathogen-microbiome interactions grows, the opportunity for new targets to be exploited will arise. Additionally, reexamining old antimicrobial targets (i.e. the cell wall) can give rise to new antimicrobial targets that have previously been overlooked. For instance, targeting the degradation of bacterial cell wall thereby preventing incorporation of new material and halting growth and division could provide a promising “untapped” approach.”
Due to the urgent need and the complexities of the research, public/private collaborations between academia or charitable organisations and industry are key to the success of antibiotic discovery.
Researchers from Utrecht University (Netherlands), Bonn University (Germany), the German Center for Infection Research (DZIF), Northeastern University of Boston (USA), and NovoBiotic Pharmaceuticals (USA) shared the discovery of a new antibiotic in a scientific paper in August 2023. Clovibactin combats harmful bacteria by targeting three different precursor molecules that are all essential for the construction of the cell wall, making it more difficult for bacteria to develop resistance against it.
The Global Antibiotic Research and Development Partnership (GARDP) and the University of Liverpool have confirmed an agreement to collaborate to advance new treatment options for newborns with sepsis. Their research has laid the groundwork for GARDP’s global clinical trial on neonatal sepsis, which will rank the safety and effectiveness of new combinations of three existing antibiotics against commonly used regimens to treat babies with sepsis.
The GARDP and Indian biopharmaceutical company Bugworks Research are also working together on a new broad-spectrum antibiotic compound. BWC0977 is targeted at treating infections caused by Gram-negative bacteria, which have become resistant to most available antibiotic treatments.
Reid concludes: “To address AMR we need a broad-based approach to drug development, that encompasses re-invigorating existing antibiotics that have significant resistance issues through combination therapies that inactivate the resistance mechanism, new chemical entities targeting previously untapped cellular pathways in the pathogen, and non-traditional approaches such as bacteriophage and immunomodulating agents.”
Christopher W Reid is Professor of Biological and Biomedical Sciences in the Department of Biological and Biomedical Sciences at Bryant University in the US. He investigates bacterial carbohydrate acting enzymes involved in Gram positive peptidoglycan metabolism and the identification of small molecule inhibitors of these enzymes as chemical biology tools and antimicrobials.