How bio-innovations could wean the world off antibiotics.
In 2020, Swedish startup Amferia received $650, 000 to commercialise a bacteria-killing hydrogel that could be used as wound patches, wound-healing granules, and medical device coatings. Its active compounds are not antibiotics but peptides, molecules that occur in plant, animal, and fungi immune systems. Antimicrobial peptides on the surface of Amferia’s hydrogel degrade the walls of the bacteria on contact, including those of antibiotic-resistant strains of MRSA, MDR E Coli, and Pseudomonas aeruginosa.
Amferia’s innovation is part of a global push to move away from antibiotics. Although they have been a central pillar in infectious disease control since the 1940s, routine use across vast animal and human populations has produced drug-resistant superbugs that cause millions of deaths annually. In 2104, the WHO concluded that global public health has reached an alarming inflection point, predicting a future where minor scratches could regularly result in major illness and death.
Bacterial resistance is natural evolution at work. In every microbial population, some bacteria will feature random genetic mutations that give them a fighting chance against antibacterial agents. These stronger strains survive and multiply while the drug eliminates weaker varieties. Eventually, the whole population becomes unresponsive to the treatment. The spread of drug-resistant mutant genes through a bacterial population is likelier when an antibiotic does not kill off enough microbes at enough speed. This give the bacterium with even marginal survival advantages a window of opportunity to proliferate.
Bacterial resistance builds up continuously, forcing researchers to devise newer drugs at a faster rate. This arms race against bacterial mutation has become a Sisyphean struggle for the medical community. For years, pharmaceutical companies have tried to keep pace with resistant strains by making novel drugs that vary only slightly in their basic bacteria-fighting mechanisms. Of the twelve antibiotics created since 2000, at least eight have led to widespread resistant strains. Large pharmaceuticals like Novartis, AstraZeneca, Sanofi, and Allergan are already jumping the ship, seeing little profit motive in developing advanced antibiotics that will become obsolete within years.
What are the alternatives to antibiotics?
New medical paradigms are urgently needed to treat infections. Luckily, the natural world is a treasure trove of medically useful compounds and mechanisms. Antibiotics themselves are genetically modified forms of naturally occurring substances in soil bacteria and fungi. Any future alternatives will also be found in the bio-resources furnished by evolution.
The most likely candidates are antimicrobial peptides of the kind used in Amferia’s hydrogel. Under electron microscopy, these molecules look like thin blades of grass. Antimicrobial peptides have shown promise in treating a range of bacteria, including biofilms which are protective substances produced by bacteria to attach to surfaces. Made up of extracellular protein and extracellular DNA, these tough bio-casings are difficult to eliminate and notorious for their ability to build up rapid antibiotic resistance. In 2019, researchers used melittin, a type of antimicrobial peptide created from the venom of the European honeybee, to eliminate biofilms formed by the bacteria P. aeruginosa in mouse wounds. Impressively, they were effective against even the most recalcitrant mature forms of biofilms.
Peptides do not encourage bacterial resistance at the same rate as conventional antibiotics do. Researchers believe this is because peptides are simply better at killing bacteria more efficiently and in a shorter time, eliminating any residual microbes that might otherwise have the chance to multiply and mutate into more dangerous strains. Four antimicrobial peptides are currently undergoing clinical trials on humans. Three others have completed the testing process, having achieved reduced infection with few side effects.
Bacteriophages, a type of virus, are another natural ally in the fight against bacterial disease. Some species look like insectoid robots with stem-like bodies, a bulbous DNA-packed head, and a ring of leg-like ‘spikes’. This terrifying physique is built to serve the organism’s voracious appetite for bacteria. The spikes act as grapples that latch onto bacterial cell walls, allowing the bacteriophage to inject its genome inside. Eventually, new phages multiply inside the bacterium, destroying it from within.
Scientists have known about the antibacterial action of bacteriophages since the early 20th century. Abandoned by the West in favour of more easily administered antibiotics, they were picked up by the Soviet Union, which became the leading centre of bacteriophage therapy research. Former Soviet states like Georgia have continued to use bacteriophages as an antibiotic alternative.
Now, bacteriophage therapy research has revitalised in the West with preclinical trials ongoing for bone, lung, gastrointestinal, blood, and wound infections. Currently, five different types are being tested in clinical trials on humans. Despite its experimental status, a growing number of hospitalised patients are being treated with phages as a last-resort treatment where antibiotics have failed. The US’ first dedicated phage therapy centre in San Diego California runs clinical trials in collaboration with companies like AmpliPhi Biosciences and Adaptive Phage Therapeutics. It also administers personalised phage treatments to patients with infections that are not responding to conventional antibiotic therapy. Because the treatment has not been approved by the Food and Drug Administration, the centre faces vast amounts of paperwork when attempting to use phage in individual emergency cases.
Veterinary medicine is where bacteriophage treatments are on the cusp of widespread rollouts. Polish startup Proteon Pharmaceuticals are among the first to make headway in this market. In 2021 they received €21 million in investment to commercialise their bacteriophage cocktail for bacterial outbreaks in finfish aquaculture. Human antibiotic resistance is tied to antibiotic overuse in agriculture, making bacteriophage treatments for farmed animals a public health priority.
Another class of drugs that offer an alternative to antibiotics is antimicrobial enzymes produced by bacteria or bacteriophages. The Vienna-based biotech company Phagomed have developed synthetic bacteriophage enzymes, called lysins, for antibiotic-resistant bacterial vaginosis. In 2021, BioNTech acquired the company to advance the technology further.
Biomaterials in anti-bacterial treatment
For anti-microbial compounds to become market-ready pharmaceutical products, they need suitable mediums that can deliver them safely to targeted areas of the body. This is where biomaterials will have an important role to play in the future of antibacterial treatments. For example, certain bacteriophages are effective against gastrointestinal infections caused by Escherichia coli and C.difficile. However, the stomach’s acidic environment is lethal to many strains. A biomaterial like Eudragit S100 polymer, algae-derived particles, or fatty liposomes can protect them from the low Ph.
Living bodies are less likely to reject biomaterials than synthetic polymers. An additional advantage is that they are naturally degradable. Today, there are a huge range of bio-material options for medical applications. Chitosan nanoparticles have shown to be effective drug delivery materials for antimicrobial enzymes that target Streptococcus pneumoniae, a cause of lung infection. Chitosan-fortified paper has been demonstrated as an effective delivery medium for bacteriophages used in treating Escherichia coli. Hydrogels based on citric acid, egg-shell membranes, and DNA nanostructures have been used to treat acute wound infections. In the 2019 study where researchers treated wound infection in mice with an antimicrobial peptide, the delivery medium was agarose, a material made from red seaweed.
The choice of biomaterial in drug delivery devices can determine whether an antimicrobial compound that shows promise in the lab can perform reliably in the clinic. Apart from protecting antimicrobials in hostile environments, biomaterials can be engineered to release therapeutics at a consistent rate and for prolonged periods at the site of infection. Controlling these factors is crucial to reducing the chances of resistance. Superbugs are more likely to emerge when therapeutic concentrations dip below an optimal amount. Blasting bacteria with high, sustained doses is essential to lowering the possibility of resistant strains.
Biomaterial choice is also fundamental to determining where and when they are released in the body. To this end, biomaterials can be engineered to respond to certain levels of pH, temperature, or light. For example, Chinese researchers have produced anti-microbial peptide-based hydrogel that ‘switches’ in response to environmental acidity. Under low pH conditions, the gel disintegrates to release the peptides to treat the infection. Otherwise, it functions as an inert material that can be loaded with additional wound-healing drugs.
R&D and commercialisation of non-antibiotic treatments
Currently, most non-antibiotic antibacterials remain at the pre-clinical (pre-human testing) stage. However, the number of live projects is promising. In 2019, Nature reviewed 407 pre-human testing trials for antibacterials. Of these, 135 focused on new drug classes including synthetic or natural antimicrobial peptides. Twenty-seven institutions were engaged in 33 projects that involve phage or phage-derived drug classes.
The biggest problem with translating peptides into clinical drugs is the high cost of synthesis, their short life in living organisms, and toxicity issues at high doses. The high costs of gaining regulatory approval from the European Medicines Agency or the US Food and Drug Administration are also an obstacle, especially since innovation is concentrated within SMEs and universities. Bacteriophage R&D lags behind that of peptides due to questions over dosage requirements, the challenge posed by the vast array of phage types, and difficulties with production, purification, and quality control. To translate exciting bio-innovations into viable therapies, more collaborative ties need to be built between small companies, universities, and large established pharmaceutical enterprises.
Matching non-antibiotic anti-bacterials to suitable bio-based materials for effective drug delivery is also an important part of the development pipieline. For this reason, collaboration between biomaterial engineers and biotechnologists is essential to commercialising these novel treatments.