Antibiotic resistance (AMR) is a growing threat to global health. According to data from the Antimicrobial Resistance Collaborators, in 2019, it caused nearly 5 million deaths, mainly in sub-Saharan Africa. This is a problem that unfortunately only promises to get worse. At a global level, concern about antibiotic resistance and the consequences that may arise from it is very high. “AMR is a huge global health, social and economic challenge that is predicted to cause $1 trillion in additional health care costs and push 28 million people into poverty by 2050,” he said. Nature Medicine Hanan Balkhi, Deputy Director-General for AMR at the World Health Organization. According to Balkhy “we need better data and evidence; we need countries to invest in strengthening their health systems; we need action in human, agri-food and environmental health; and we need to develop new antibiotics”.
The phenomenon of antibiotic resistance is so alarming that it is defined as a “threat to patient safety”. In Italy in 2021 62,833 pathogens were isolated and the percentages of resistance to the main classes of antibiotics remain high, so much so that our country is in the black jersey for the incidence of resistant bacteria, positioned only after Greece and Romania. It is estimated that in 2050 bacterial infections will cause 10 million deaths a year worldwide, exceeding deaths from cancer. Complex problems to deal with and the idea of solving them all borders on the impossible. However, experts around the world are refusing to surrender to AMR and are exploring new tactics.
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Risky investments and little profit
Despite the urgency, there has been little progress in the innovation of new antibiotic drugs over the past two decades. According to a report by the Biotechnology Innovation Organization, more than 82 percent of all antibiotic approvals occurred before the year 2000. The last new class of antibiotics, the oxazolidinones, were developed in the early 2000s. Pharmaceutical companies and biotech companies have neglected antibiotics due to the associated economic risk and low market profitability. It also happens because it is a class of drugs that is used for short periods and whose prescription by doctors is strongly discouraged precisely to avoid worsening the problem of antibiotic resistance.
New payment methods
How to solve this problem? Some countries, for example the UK, are experimenting with innovative payment models, such as one based on ‘subscription models’ whereby a pharmaceutical company receives an annual payment for a specific product, regardless of the volume of medicine prescribed. In the United States, the Pasteur Act, if passed, would establish a value-based pricing system that could promote the development of new antimicrobials. The text refers to the “significant challenges” that a company faces in the research and development of antibiotics, particularly in the advanced stages of development. To address these challenges, the text suggests that there must be tailored incentives to boost innovation and stimulate further investment. The tailor-made incentives mentioned in the text are called “pull incentives” designed to ‘attract’ or encourage companies to invest in the R&D of new products. The annual subscription method is also an ‘pull incentive’ as companies would be attracted by the idea of having a guaranteed income, regardless of the number of doses sold.
In search of the unknown
Despite all the advanced approaches to developing new antibiotics, most of those on the market still come from microorganisms, including fungi and bacteria. However, Elizabeth Shank, head of the Department of Systemic Biology at UMass Chan Medical School, believes many potential antibiotics from bacteria are being overlooked. “From the genomic sequences of the bacteria, we can see that they have the ability to make many interesting compounds that we have potentially never characterized,” says Shank who is trying to grow the bacteria together. “We are using coculture to try to stimulate the production of new metabolites that could lead to new antibiotics,” Shank said.
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Genetic engineering
Another approach being worked on for the production of new antibiotics is based on synthetic chemistry. For example, Brady and his colleagues have been looking for antibiotics that might bind to menaquinone, a form of vitamin K that plays a key role in the energy metabolism of many bacteria. The scientists used algorithms to predict the groups of genes that could produce small molecules capable of targeting menaquinone, and then synthesized them. Some of the antibiotics derived from this approach have even killed methicillin-resistant Staphylococcus aureus.
At Rockefeller University, the organic chemist Sean Brady and his colleagues are taking a bioinformatics approach to identify and synthesize new natural products from the genome of bacteria. In a recent study, Brady and her team discovered cilagicin, a potential antibiotic that has been shown to be effective against hard-to-treat pathogens and resistant to resistance development. Researchers at the University of California, Santa Barbara are experimenting with the use of conjugated oligoelectrolytes as potential antibiotics. These small synthetic molecules have been engineered to interact with bacterial membranes and have proven effective against a wide range of microorganisms.
The bioinformatics approach and Artificial Intelligence
Artificial intelligence (AI) is also entering the field in the search for new antibiotics. “AI can be harnessed, applied to large data sets that we can create, to discover and design new antibiotics for some of the most problematic pathogens threatening humanity,” he said Jim Collins, professor of medical engineering and science at the Massachusetts Institute of Technology. Working with a TED initiative called The Audacious Project, Collins and his colleagues launched the Antibiotics-AI Project to develop new classes of antibiotics.
The AI turbocharges research
By applying AI to antibiotic discovery, scientists can explore more compounds and do it faster. In the past, a large pharmaceutical company may have analyzed a million compounds in search of a new antibiotic. Using AI, Collins and his colleagues analyzed 110 million molecules in just 3 days, which led to the discovery that halicin, previously studied as a treatment for diabetes, has antimicrobial properties. “It was a huge reduction in both resources and time,” Collins says.
Aiming for new targets
Traditionally, the search for new antibiotics has focused on drug-resistant pathogens or the search for broad-spectrum antibiotics. ‘Targeted’ antibiotics can be developed for some drug-resistant pathogens, such as carbapenem-resistant Acinetobacter baumanii, which is on the World Health Organization’s list of priority antibiotic-resistant pathogens. This targeted approach can also be applied to various types of treatments, including engineered bacteriophages (viruses that naturally infect and kill bacteria), novel antibodies and drug-conjugated antibodies. But now researchers are looking for alternative strategies.
From a US Army design
The sources of tomorrow’s antibiotics could come from unexpected research, such as a US Army project that used trace electrolytes to recharge cell phones in a battlefield. “Bacteria are energy cells, and conjugated oligoelectrolytes have been engineered to insert into bacterial membranes and function as electron carriers to potentially power electronic devices,” says the geneticist. Michael Mahan of the University of California, Santa Barbara. Conjugated oligoelectrolytes (COEs) are small synthetic molecules that “share a modular structure that can spontaneously interact with the lipid bilayer,” she explains.
Mahan and his colleagues have repurposed COEs as potential antibiotics. “From a screening of a broad range of COE chemical variants for antibacterial activity and low cytotoxicity in cultured mammalian cells, COE2-2hexyl was the leading candidate,” she says. Despite the considerable work to be done on COE2-2hexyl, Mahan and his colleagues showed that it can attack a wide range of microbes, and did not trigger resistance in bacteria.
A new sensitivity test
Mahan and his colleagues have also developed a new antibiotic sensitivity test, which they say better mimics the action of antibiotics in the body. Using this test, they found that some U.S. Food and Drug Administration-approved antibiotics were effective at treating infections that were thought to be resistant to multiple drugs. These readily available antibiotics “are not being prescribed because the standard test doctors rely on indicates they won’t work,” says Mahan. By simulating conditions in the body, the new test identified several effective antibiotics that were rejected by the standard test. As a result, some of the antibiotics in the current antimicrobial toolbox may be more useful than generally believed. As Mahan concludes: ‘The new test could improve the way antibiotics are developed, tested and prescribed.’
Ensure equity of access
But discovering and developing new antibiotics is not enough. Researchers agree that scientific breakthrough in the research and development of new antibiotics should reach those who need it most, including low- and middle-income countries by implementing what some refer to as a ‘last mile delivery approach’ “. A complex goal to deliver for new antibiotics that will require close partnerships with governments, regulators, private institutions and civil society. If this close partnership fails to resolve the antimicrobial resistance (AMR) crisis, some aspects of Health care could return to the past. As Shank observes: “150 years ago, you could die because you scratched your finger and caught bacteria.” This is a past that nobody wants to go back to.