In the battle against antibiotic resistance, some scientists are trying a new approach: re-sensitizing bacteria to drugs they no longer respond to, so existing antibiotics can hit the mark again.
“It is a sustainable and direct approach to the problem of antibiotic resistance,” said Fredrik Almqvist, professor of organic chemistry at Umeå University in Sweden. “New antibiotics require a lot of money to develop. We are developing compounds that enhance the antibiotics we already have, which is much more cost-effective . “
These new compounds do not kill bacteria . Instead, they selectively disarm them, giving the antibiotics a chance to show up and finish the job. “They sensitize the pathogen and restore the effectiveness of antibiotics,” said Prof. Almqvist. “Is incredible”.
Much of Prof. Almqvist’s research focuses on tuberculosis, an infection that kills 1.6 million people each year. Some strains of the disease, such as Mycobacteria tuberculosis (Mtb), show formidable resistance to antibiotics, making them particularly difficult to treat.
However, Prof. Almqvist has joined forces with molecular biologist Christina Stallings, from the University of Washington, USA, to develop chemical compounds that break down the defenses of these drug-resistant strains, inhibiting the formation of biofilm. , a matrix of molecules that surrounds bacterial cells, providing protection against external attacks. Enclosed in biofilm , bacteria can be up to 1,000 times more resistant to antibiotics, but in the presence of Prof. Almqvist’s compounds, drug-resistant tuberculosis bacteria are rendered defenseless. “The tuberculosis bacteria are there and alive, but they do not form a biofilm,” said Prof. Almqvist. “Without a biofilm, they die from the antibiotic.”
Prof. Almqvist says that the compounds discovered in his laboratory, known as Mycobacterial Tolerance Inhibitors (ITNs), are promising in two ways: they block Mtb’s defenses against antibiotics and reduce treatment times for all TB patients from 6-9 months to just one month. His biochemical company, Quretech Bio, is ready to start testing Mtb compounds in animal models.
Breaks antibiotic resistance
Methicillin- resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE) superbugs have also had their antibiotic resistance reversed in Professor Almqvist’s lab after exposure to antibiotic resistance breakers (ARBs). “These are infections that can become very dramatic in a matter of hours if not treated effectively,” said Prof. Almqvist.
He explains that ARBs can control life-threatening infections by restoring the potency of antibiotics that have lost their edge. “We see this as a direct approach to a really big problem,” he said.
As part of a project called QTB4AMR, it is developing a methodology to synthesize compounds that can then be tested and developed in ARBs. The compounds, some structurally similar to each other, are being evaluated for their ability to “strongly synergize” with existing antibiotics at the rate of 100 to 500 new compounds per year.
“We hope to motivate further development,” said Prof. Almqvist, admitting that it will take “a lot of investment” and “a lot of commitment” from both academic research bodies and pharmaceutical companies before their ARBs produce new treatments for drugs. patients.
To some extent, antibiotic resistance is a natural phenomenon . Bacteria mutate rapidly, and mutant strains that are able to survive a dose of antibiotics have an immediate evolutionary advantage. But our misuse and abuse of antibiotics is accelerating the resistance process , putting us in a race to stay ahead of the superbugs. The resistance is a global catastrophe that kills 700,000 people every year. If solutions are not found quickly, drug resistance is expected to cause 300 million premature deaths worldwide in the next 35 years.
Research to find new antibiotics has stalled for the past 30 years. Of the products being tested today, only a few are classified by the World Health Organization (WHO) as innovative treatments with new modes of action that will add value to the arsenal of existing treatments (as opposed to reformulations of existing ones). existing drugs). Most alarmingly , none of the new antibiotics in development are expected to be effective against the most dangerous forms of antibiotic-resistant bacteria .
Cost
So what is the lack of innovation due to? Designing a new formulation is an expensive business, but there is pressure on physicians in health organizations around the world to prescribe antibiotics wisely. In other words, the world needs drugs that can stay on the shelf until they are absolutely essential, which is not an incentive for pharmaceutical companies to invest billions in research. In fact, between 2003 and 2013, less than 5% of venture capital investment in pharmaceutical R&D went to antimicrobial development . Also, unlike many other life-saving drugs, antibiotics are generally used in the short term and patients expect to purchase them cheaply.
“We pay millions of euros for some therapies, but we hope that antibiotics, which are life-saving drugs, will cost only a few euros,” said Mariana Pinho, head of the bacterial cell biology laboratory at the Universidade Nova de Lisboa. He added: “So the idea of taking drugs that have already been approved for clinical use and reusing them is very attractive. ” “Re-sensitizing bacteria is much more profitable than developing new antibiotics .”
Like Prof. Almqvist, Profa. Pinho is immersed in the search for ways to increase the performance of existing antibacterial drugs. While he emphasizes that the search for new antibiotics must never cease, he also believes in the potential of combination therapies, where depleted antibiotics are restored to full function after being mixed with new smart-acting compounds.
His ChronosAntibiotic project focuses on Staphylococcus aureus , one of the most common multi-resistant bacteria in Europe. Staphylococcus aureus causes a number of conditions, some of them serious, collectively known as staph infections.
Using super-resolution microscopy, he studies the mechanisms of bacterial cell division, looking for the moments in the cell cycle when the microbe is most susceptible to the actions of antibiotics. Pinho believes that the addition of compounds aimed at breaking resistance will allow antibiotics to use these windows of opportunity to best effect. “We want to find those weak spots in the cell cycle,” he said. “These are our long-term goals.”
Profa. Pinho is part of the team that has found a chink in the armor of resistance to the drug MRSA. A small molecule called DNAC-1, discovered by Pinho’s collaborators, has been shown to intensify the effect of the antibiotic oxacillin by damaging the microbe’s cell membrane. With the membrane disrupted, the antibiotic is free to enter and kill the cell.
The cell membrane is only one of the potential targets for the action of new compounds. All cellular components and metabolic actions are being carefully examined for their susceptibility to damage and disorders.
To follow his lab’s findings, Pinho is building a library that pairs bacterial genes known as reporters , with compounds that have been found to inhibit the expression of these genes, thus leaving the cell sensitive to antibiotics.
Its initial goal is to deepen understanding among the research community of the cellular pathways that lead to drug resistance. “Just understanding biology is an important start,” he said.
By 2023, he hopes to have found useful reporters in the discovery of antibiotics that can be turned into a new drug or a smart compound to resurrect an existing one. “I would be very happy if, in the course of my life, I could contribute to the development of a new drug,” she said.
Four bacterial defenses against antibiotics
1. Cloak of Invisibility
The bacterial organism changes its physiology so that the antibiotic cannot find its target. Some bacteria actively alter the structure of their cell wall to make it invisible.
2. Pump and discharge
Bacteria regularly expel harmful compounds from their system using a protein to pump them out of the cell. These effluvia pumps have evolved to now actively eliminate antibiotics.
3. Protein shield
The bacteria’s proteins stick to the antibiotics or the drug target inside the bacterial cell. That protein then prevents the antibiotic from successfully binding to its target.
4. Counterattack
Some bacteria have evolved to produce defensive enzymes. They destroy or modify the antibiotic molecule and render it completely ineffective.
Artículo original
This article was originally published in Horizon, the EU Research and Innovation Magazine
