Addressing the Antibiotic Resistance Problem
More and more antibiotic-resistant strains of bacteria are evolving. They pose a major threat to public health and will drastically change our futures if we cannot find new solutions to defeat them.
Antibiotic-resistant infections can affect anyone, anywhere - it’s a universal issue that undermines modern medicine.
“AMR is a slow tsunami that threatens to undo a century of medical progress.”
Dr Tedros, Director General of the WHO
Many of the few new antibiotics in clinical development are “me-too” drugs that belong to existing classes of antibiotics and do not provide a substantial improvement over existing drug products when it comes to combatting established resistance.
But action is being taken. Governments, organisations, businesses and scientists are developing new solutions to tackle the problem of antibiotic resistance.
Let’s look at some novel approaches that are being researched and developed as potential solutions against antibiotic-resistant bacterial infections.
Microbiome-based Therapies
Vedanta Biosciences is company that approaches drug development with the hypothesis that bacteria cause infection when a patient’s own microbiome is depleted.
Using global research conducted on the microbiome it is identifying the “good” bacteria of our microbiome as well as those which can trigger targeted immune responses.
The human body is an ecosystem. Trillions of microbes call us home. They form the human microbiome, which performs critical functions that preserve our health including modulating our immune system and providing colonization resistance against infectious pathogens. Alterations of the human microbiome are increasingly recognized as a key factor in development of immune and infectious diseases.
Vedanta.
This research has informed the development of two bacterial consortia therapeutics as potential treatments for certain bacterial infections.
VE303, which is being developed for high-risk Clostridioides difficile (CDI) infection and is currently in a Phase 2 clinical trial.
VE707, which is a preclinical discovery program for the prevention of infection and colonisation recurrence of several multi-drug resistant organisms (MDROs) including carbapenem-resistant Enterobacteriaceae (CRE), extended-spectrum beta-lactamase producers (ESBL), and vancomycin-resistant Enterococci (VRE).
Both are administered as a lyophilised powder in oral capsule form. They are produced from pure, clonal bacterial cell banks, not faecal donor material!
Once administered the bacteria can enter the gastrointestinal tract and colonise the intestine. This shifts the composition of the gut microbiota, which could protect against the colonisation of certain intestinal infectious pathogens.
Read more here.
Bacteriophage Viruses
Bacteriophages are naturally occurring viruses that can infect and kill bacteria using different mechanisms to antibiotics.
Some scientists are now altering them in attempts to use them against certain bacterial infections.
For example, a team of biological engineers at the Massachusetts Institute of Technology (MIT) have successfully programmed bacteriophages to kill different strains of E. coli. This was achieved by making mutations to a viral protein that binds to host cells via LPS receptors. The mutations were targeted to regions that would have minimal effect on the protein structure but would change the bacteriophage’s binding interaction with the bacteria. Some of the mutated bacteriophages were able to kill strains of E. coli with mutated or missing LPS receptors - strains which the original bacteriophage could not.
Halicin
A team of researchers at MIT recently used a deep learning model to screen a library of molecules and:
Predict which would be effective against E. coli.
Only show them molecules that look different from conventional antibiotics.
The model identified 100 candidates for physical testing, and one molecule, which was later called halicin, demonstrated potent antibiotic activity.
In subsequent tests conducted in mice, halicin showed broad-spectrum antibiotic activity (including against a strain of Clostridioides difficile and Acinetobacter baumannii).
The next step is to get halicin into clinical trials and to use the model approach to find more new antibiotics.
Read more here.
Peptidomimetics
Scientists from the Rennes University and the French National Institute of Health and Medical Research (Inserm) are currently transforming a bacterial toxin into an antibiotic effective against various Gram-positive and negative bacteria.
"It all started with a fundamental discovery made in 2011. We realised that a toxin produced by Staphylococcus aureus whose role is to facilitate infection is also capable of killing other bacteria present in our body. What we had identified was a molecule with dual toxic and antibiotic properties. We thought that if we could separate these activities, we would be able to create a new antibiotic non-toxic to the body. A challenge that we accepted!”
Brice Felden, Director of the Bacterial Regulatory RNAs and Medicine laboratory in Rennes.
This discovery led to the development of a new family of peptidomimetics - cyclic heptapseudopeptides. They are inspired by the natural bacterial toxin, whose structure was modified to develop potential antibiotics.
A short study demonstrated that two of the peptidomimetics generated were effective against two resistant bacteria - Staphylococcus aureus and Pseudomonas aeruginosa - in mouse models of severe sepsis or skin infection, while not causing any harm to the mice. After being left in contact with the animals for several days, no drug resistance was observed. Additionally, the peptidomimetics did not exhibit toxicity for human erythrocytes and kidney cells.
The heptapseudopeptide’s bactericidal activity is due to its dynamic association with bacterial lipid bilayers, which induces membrane permeability, leading to bacterial death.
The study authors wrote:
“We have identified potential therapeutic agents that can provide alternative treatments against antimicrobial resistance. Because the compounds are potential leads for therapeutic development, the next step is to start phase I clinical trials.”
Read more here.
The Universal Bacterial Sensor
The Universal Bacterial Sensor isn’t a treatment for bacterial infections but I’ve mentioned it because it may help address one of the major causes of bacterial antibiotic drug resistance; the misuse of antibiotics.
The Universal Bacterial Sensor is a diagnostic tool that rapidly identifies the class of bacterial pathogen causing an infection (Gram-negative, Gram-positive, or Gram-indeterminate) in minutes.
The results from a rapid diagnosis can inform the treatment strategy and reduce inappropriate use of antibiotics. For example, the results could allow the use of antibiotics to be avoided if the infection is viral rather than bacterial or reduce the use of the wrong types of antibiotic according to bacterial class.
The effect of reducing the number of antibiotics being prescribed inappropriately could be huge since it’s estimated to account for as much as half of global antibiotic use.
“Detailed global estimates are lacking but in countries of the Organisation for Economic Co-operation and Development (OECD), as many as half of all antimicrobials used in human health care can be considered inappropriate.”
By reducing inappropriate usage the sensor could help prolong the efficacy of existing antibiotics.
The Universal Bacterial Sensor was developed at Los Alamos National Laboratory. Read more about it here.
Partnerships to support Antibiotic Development
To support the discovery and development of new antibacterial products that help address the threat of antimicrobial resistance, several partnerships have been established that focus on the threat of AMR, invest in innovative new antibacterial treatments and bring together key stakeholders. These include:
Combating Antibiotic-Resistant Bacteria Biopharmaceutical Accelerator (CARB-X)
The Global Antibiotic Research and Development Partnership (GARDP)
Investment and other support for new antibiotic solutions is key due to the costly drug development and clinical trial processes.
The Stakes
Finding new solutions to the AMR threat is important because the impact of AMR could be worse than that caused by the COVID-19 pandemic in terms of the number of lives lost and the economic costs.
Although AMR is growing, we know it is, so it is both a predictable and preventable crisis. We have an opportunity now to get ahead. In the long term that’s the most cost-effective option and one with the potential to save millions of lives.
Sources
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Cover photo credit : MIT News