The University of Pennsylvania finds peptides effective against microorganisms that resist current treatments in animals that have already disappeared.
In a few years, dying from frequent bacterial pneumonia or a common infection could be common. Of all the threats facing humanity, one of the top 10 is antibiotic resistance, according to the World Health Organization (WHO). According to data from its specialized group (IACG), drug-resistant diseases could cause more than 10 million deaths annually in 2050, more than double what is now. Spanish biotechnologist César de la Fuente, principal investigator of the laboratory that bears his name, also known as the Machine Biology group at the University of Pennsylvania, has been searching for more than a decade, with the help of artificial intelligence and deep learning. , new molecules that microorganisms have not yet learned to survive. He has found them, and resurrected them, in our Neanderthal and Denisovan ancestors. Now, according to him, he publishes Nature Biomedical Engineering, in extinct animals, such as the mammoth. A race against the clock in which everything can hide a solution, from missing species to microbial dark matter, microorganisms that have left genetic material in any medium, but that have not yet been grown in the laboratory.
If the rate of generation of resistance to antibiotics continues as before, the health of humanity will go back a century, to the era before penicillin. Preventing this gigantic step backwards is César de la Fuente’s mission and his laboratory.
The discovery of compounds with antibiotic potential in Neanderthals and Denisovans opened the door to crossing the border of what exists and searching in disappeared species. “It encouraged us to ask ourselves: why not explore all the animals, all the extinct organisms available to science?” explains De la Fuente, considered one of the top 10 researchers in the world.
The key has been technology, whose fusion with biology allows us to reveal worlds that have until now been hidden or already disappeared. “To be able to explore hundreds of proteomes [conjunto completo de proteínas elaboradas por un organismo] At the same time, we have had to develop a more powerful artificial intelligence model than the one used previously. We created a deep learning model that combines the latest in artificial intelligence and machine learning [aprendizaje automático] based on neural networks”details the researcher, who named the system APEX (Antibiotic Peptide de-Extinction).
“It allowed us to explore organisms throughout evolutionary history, including the Pleistocene and Holocene periods. “We investigate many species, from extinct penguins to the mammoth or the giant sloth that Charles Darwin discovered on one of his expeditions to Patagonia.”he relates.
From this enormous work, a total of 10,311,899 peptides (short chains of amino acids linked by chemical bonds) were extracted and 37,176 sequences with broad-spectrum antimicrobial activity were identified. Almost a third of them (11,035) are not found in existing organizations. “As we are bringing back to life molecules that existed thousands of years ago, contemporary pathogenic bacteria have never seen them and most likely do not have resistance mechanisms”Explain.
Many of the sequences have demonstrated antimicrobial efficacy in vitro (culture dishes or Petri dishes) and some have been able to kill contemporary pathogenic bacteria in mouse models of preclinical relevance with an efficacy comparable to that of antibiotics available today and with lower doses. . They have been tested with skin access and deep infections of the thigh.
Its origin, until now unknown, has forced the team to even develop new terminology. In the case of the extinct ancestor of the elephant, the small protein discovered is called mammothsin; that from Mylodon darwinii (the ancestor of the sloth discovered by Darwin), mylodonina; and equusina is the one found in the current zebra and its ancestors.
The team has also experimented with the combination of several molecules from the same species or two similar ones (mammoth and ancient elephant) in case they enhanced their antimicrobial activity against the singular protein. It also remains to be seen if microorganisms develop resistance to these new compounds and in how long. “It’s on the list.”specifies De la Fuente.
“This work allows us to go back in time and find different sequences, a diversity of molecules that can help us deal with antibiotic resistance and, perhaps, other problems. We always think of DNA to explore life, but this work proposes to start using molecules as sources of evolutionary information, to see how they progressed or what type of mutations occurred over time, to learn more about our own immune system and, perhaps, predict how it will evolve”he concludes.
The next step is to formalize agreements with pharmaceutical companies and surpass the preclinical level in mouse models to move on to human trials or even create a company arising from César de la Fuente’s laboratory to complete what has been achieved at an academic level.
Luis Ostrosky, head of infectious diseases and epidemiology at UTHealth Houston (University of Texas Health Science Center) and not involved in De la Fuente’s research, praises the line taken in the face of an emergency that he considers real. “We are in a very dangerous time in the history of medicine because antimicrobial resistance is increasing. In everyday medical practice we find infections that are not treatable with the antibiotics that exist now and that is very serious because medicine depends on the use of antibiotics for things as routine as surgeries, therapies or transplants. “We are reaching the post-antibiotic era, when we will no longer have resources that work and we are constantly looking for new ones.”
In this sense, the researcher, trained at the National Autonomous University of Mexico, defends all lines of research. “The best antibiotics we have had in the history of medicine come from nature”highlights to indicate findings in plants, insects and other animals, such as the shark. “This type of research [la del César de la Fuente Lab] I have always found it very interesting. “We are seeing antibiotics in extinct species that have not been present in nature for thousands or millions of years, so they have not suffered evolutionary pressure,” points out
Ostrosky highlights that it is a permanent career that has an added difficulty: “Antibiotics are not good business for the pharmaceutical industry because their courses are generally very short: patients heal quickly and in the pharmaceutical industry the money is in chronic diseases. We constantly see them leave the market after 10 years and come back in and out. “We need other types of incentives that give us the security of having the antibiotics that we will need in the future.”
The specialist points out government support, which has already been implemented in Europe and the United States, or a “subscription model” so that companies do not depend so much on sales and that it represents a fixed incentive. “There are many economic models, but, at this moment, we definitely need a change of way of thinking in the pharmaceutical industry”. In this sense, he advocates for the World Health Organization to take a more active role and for the collaboration of North American and European agencies.
He defends this need because he considers the WHO warning “correct” and “realistic.” “If no action is taken, we could see a world where it would be unsafe to have surgery or administer chemotherapy, which reduces patients’ defenses. Unfortunately, it is not uncommon to have end-of-life conversations with some patients who have infections that are not treatable.”
