Pioneering strategies for a “post-antibiotic” era: from prevention to novel therapies

Pioneering strategies for a “post-antibiotic” era: from prevention to novel therapies

Introduction: From a life-changing discovery to a modern-day emergency

Since their discovery in 1929, antibiotics have marked a before-and-after in human and veterinary healthcare, becoming essential in the prevention or treatment of bacterial infections. Indeed, the discovery of Penicillin marks a true turning point in human history, finally doctors could completely cure infectious disease. However, unfortunately the story of Fleming’s accidental discovery of this life-changing medicine overshadowed his findings that predicted their potential to develop resistance.

Today, the misuse and overuse of antibiotics have turned what started with laboratory observations into a pressing reality. Bacteria have learned to outsmart antibiotic medicines, causing infectious disease to persist. Known as antimicrobial resistance (AMR), this natural process occurs over time due to genetic changes in pathogens, but its emergence and spread has been accelerated by human activity. Notably, in 2019 AMR accounted for 1.27 million deaths globally, and according to the United Nations is set to rise to 10 million by 2050, to become the leading cause of death worldwide.1,2

Across the globe, numerous alternative strategies are being explored to prevent, diagnose, and treat infectious diseases and tackle this critical situation. But what strides have we made?

Assessing the current AMR landscape

Back in 2015, at the World Health Assembly, UN member states adopted a resolution that committed to the development and implementation of national action plans against AMR. As of November 2023, 178 countries had formulated their own AMR national action plans.1 These consider AMR as a complex problem that requires both sector-specific as well as coordinated actions across the  human health, food production, animal, and environmental sectors, namely, the One Health approach. Evidence indicates that meaningful and impactful changes are being achieved as a result of this.

For example, following a rise in drug-resistant infections of Carbapenemase Producing Enterobacterales (CPE), Ireland implemented its first national action plan (iNAP1) from 2017 to 2020. This plan led to the creation of the National Public Health Emergency Team for CPE in November 2017, which provided crucial guidance, support, and direction for national-level surveillance and management of CPE. As a result, diagnostic capabilities were significantly improved (e.g., 28,603 CPE surveillance samples were tested in July 2017, surpassing the monthly target of 25,000), and infection rates decreased (e.g., 398 new patients in the first 35 weeks of 2021, compared to 436 in the same period of 2020). Thus, by developing and implementing effective, One Health-aligned containment strategies, a robust foundation for proactive CPE management was established.3

Today, as nearly a decade has passed since the resolution, therapeutic, diagnostic, and preventive technologies have been experiencing exponential growth. 

Exploring the pathways and who’s working on them

Hello Tomorrow’s research in this area, stemming from our unique position in the deep tech innovation ecosystem, unveils three key pathways that are becoming essential for fighting AMR. The first line of action involves preventive measures utilising advanced antimicrobial technologies. Second, there is a focus on developing affordable, rapid antibiotic sensitivity testing using advanced molecular methods. Lastly, we must continue to pursue new anti-infectives that are resilient to pathogen resistance. 

Prevention: As the saying goes, better safe than sorry. Thus, the first line of action against AMR is avoiding infection. Allocating resources towards preventative measures can alleviate the disease burden within a population, consequently diminishing the demand on antimicrobials and their indiscriminate use. These measures not only refer to simple hygiene and sanitation practices, but also advanced antimicrobial technologies.

Within the Hello Tomorrow network, several deep tech startups are at the forefront of developing preventative solutions. For example, SPARTHA Medical, one of our 2024 Deep Tech Pioneers (DTP), is developing a personalised multifunctional antimicrobial coating consisting of polyelectrolytes. The uniqueness of the system relies on the self-assembly of these patented polymers, such as polyarginine and hyaluronic acid, that create electrostatic interactions with bacteria and destroy them by contact. It has shown long-lasting antibacterial effects in in vitro models of recurrent infection, and high potential to combat several series of antibiotic-resistant infections. Being derived from natural polymers, the solution is not based on antibiotic compounds, and is biocompatible with and applicable to all types of surfaces. This enables a wide range of uses, from inert and complex surfaces to living tissues, providing a new avenue for disinfectants, which are usually toxic (even alcohol is harmful for the skin) and are not ideal for wound healing.

Another startup from our 2024 Deep Tech Pioneer selection that stands out is AvantGuard, who are aiming to replace topical antibiotics with a proven, safe, and nature-inspired biocide for infection prevention. Their innovative solution is based on the cell biology of neutrophils which has no history of resistance generation. These white blood cells kill pathogens by creating hypochlorous acid, an inherently unstable compound that they have managed to solubilise through N-halamine chemistry. Under development at Auburn University for the last 30 years, N-halamine chemistry had still not seen commercial success. Now, they leverage it to covalently bind to the chlorine in hypochlorous acid, effectively turning it into an antibiotic that is only released in the presence of a negatively charged cell wall (i.e. bacteria, virus, fungi). Hence, the AvantGuard 1stAid is an antimicrobial, anti-inflammatory, anti-adhesion coating that comes in “wet” or “dry” forms. The “wet” versions incorporate the technology into a hydrogel to maintain moisture in the wound bed, whilst the “dry” versions are in woven materials such as bandages.

However, if these preventive measures fall short, there remains another step before resorting to antibiotics that may no longer be effective.

Diagnostics: Currently, one of the main reasons that antibiotics are overprescribed is the lack of suitable point-of-care diagnostics. Nearly half of all antibiotic treatments worldwide start without proper diagnosis, leading to an incorrect drug prescription.2 Current diagnostic methods are culture dependent, and can take between 24 & 72 hours to deliver results.4 Newer molecular tests, however, can provide results within a few hours but are limited due to their high cost.

Still, technological progress is being made to achieve affordable, rapid antibiotic sensitivity testing. This is the case of APLEX Bio, a 2024 Hello Tomorrow DTP which aims at making advanced molecular testing available to everyone. They provide a next generation hyperplex PCR (hpPCR) method that can measure more than 100 targets concurrently with state-of-the-art sensitivity and specificity (i.e. dPCR-grade sensitivity, and NGS-grade single nucleotide specificity). Powered by their technology Nanpixels, padlock probes and RCA-based molecular counting, they ensure results within 4 hours. Moreover, the hpPCR kit and software can be seamlessly integrated into existing lab infrastructure. 

Therapeutics: The loss in efficacy of existing antibiotics as a result of AMR has created an ongoing need to replace the therapeutic pipeline. A report from 2016, addressing the effective management of AMR, estimated that 15 new antibiotics would be needed over a decade, with at least four of them being novel, breakthrough products targeting the bacterial species of greatest concern (e.g. pathogens designated by the acronym ESKAPE: Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species).4 However, in reality, the number of newly approved, ground-breaking antimicrobial treatments has declined over time, with only 16% of them being classified as novel.2 A big reason behind this trend is the lack of a global market that guarantees sustainable revenues, which is required in order to finance research, commercialization, and large-scale production. Notably, it currently takes from 10 to 15 years to develop innovative antibiotics, with only one in 30 reaching patients, often reporting resistance within 2-3 years post-market entry.5 

Fortunately, emerging technologies are paving novel pathways, with potential resistance-preventing benefits. Here, we highlight the work of Arivin therapeutics, a spinoff from Aalto University & University of Helsinki, and a 2024 Hello Tomorrow DTP. Rather than targeting the pathogens themselves, they employ strategies that directly neutralise the toxins used to initiate and propagate infections. Consequently, the host’s inflammatory responses are alleviated, enhancing immune reaction, and complementing standard-of-care antibiotics. Such strategy is built upon the use of antitoxins with in vitro and in vivo efficacy towards gram-negative top-priority pathogens (i.e. Pseudomonas aeruginosa and Acinetobacter baumannii). The major advantage of the therapy is that it does not encounter resistance development by bacteria, overcoming a current significant design obstacle.

Another approach in this regard is the work carried out by PHIOGEN. This 2024 Hello Tomorrow DTP is harnessing the natural killing ability of bacteriophages to develop a next generation of anti-infectives. Traditional phage therapy has only been able to treat patients individually, but Phiogen brings a new technology platform to create broad-spectrum antimicrobials. Through their proprietary methodology, they curate the phages to have superior anti-bacterial abilities, training them against resistant bacteria. This results in the development of predictive phage cocktails capable of overcoming resistance.

Finally, of course, we must not forget the power of Artificial Intelligence to identify and develop new molecules, significantly reducing discovery timelines and cost estimates. In fact, a report from March 2022 found that the pipeline of AI derived drugs clearing discovery and preclinical timelines is expanding at a rate of 40% per year. 

Future outlook and conclusions

The use of novel technologies to combat AMR has become increasingly apparent. While effective antibiotics still exist, resistance is constantly increasing. Hence, strategies will have to be deployed at each step of the care circuit. Until then, a balance must be struck between implementing novel strategies to tackle AMR in the long-term, while encouraging the correct prescription of antibiotics in the short term.

Advanced preventative measures are one of the already-available solutions. With an easier access-to-market than novel therapies, these biocompatible antimicrobials can already be leveraged to support the healthcare system, reducing nosocomial infections. In the mid-term, suitable point-of-care diagnostics are poised to bridge the gap from current gold standards, in terms of both time and cost. Ultimately, supported by enabling technologies, replacement therapies for antibiotics are expected to emerge and gain market approval, and ideally, these therapies will be based on mechanisms of action that do not create resistance.

Nevertheless, until these strategies have been thoroughly developed, regulated, and made commercially available, it remains critical to monitor the correct usage of existing antibiotics (e.g. adhere to recommended dosage and timing, avoid sharing or saving, follow-up with healthcare professionals, etc.). It is also essential that healthcare professionals adhere to evidence-based guidelines for prescribing and administering them. Moreover, any forthcoming antibiotics that may become accessible, should also be used wisely and reserved as a last resort, to prevent the onset and proliferation of bacterial resistance to them.

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Mariona Vidal Picamoles
Mariona Vidal Picamoles
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Florence Oates
Florence Oates
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Senior Editorial Specialist
Alizée Blanchin
Alizée Blanchin
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Director & Partner – Consulting

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