Cresomycin, a synthetic antimicrobial molecule highly effective against multidrug-resistant bacteria.

Today, the lack of effectiveness of drugs designed to combat bacteria is a problem that requires an urgent solution. Finding new molecules that address antimicrobial resistance has become a priority. WHO has already calculated that for By 2050, 10 million people will die from this cause every year.. According to recent data, this problem claims four times more lives of Spaniards per year than road accidents.

A new antibiotic created by the team Harvard researchers It overcomes the mechanisms of antimicrobial resistance that have rendered many modern drugs ineffective and are the cause of a global public health crisis of which the death toll is the iceberg.

CresomycinA new synthetic molecule demonstrates robust effectiveness against multiple evolutionarily divergent forms of antimicrobial resistance, according to a study published in the latest issue of the journal. The science. By structurally analyzing how antibiotics bind to the ribosomes of different bacterial species, the researchers developed a new antibiotic molecule that adopts the precise conformation required for ribosome binding.

A team led by Andrew Myers, Emory Houghton Professor of Chemistry and Chemical Biology, was able to create a compound that kills many strains of drug-resistant bacteria, including Staphylococcus aureus And Pseudomonas aeruginosa.

“We still don’t know whether cresomycin and similar drugs are safe and effective for people. Our results already show significantly improved inhibitory activity against a long list of pathogenic bacterial strains that kill more than a million people every year compared to clinically approved antibiotics. “Myers said in a statement.

It’s clear what we’re talking about. “Antibiotics are the foundation on which modern medicine is built,” says co-author and graduate student Kelvin Wu. “Many advanced medical procedures, such as surgery, cancer treatment and organ transplantation, cannot be performed without antibiotics.”

What is the new antibiotic?

The new molecule binds better to bacterial ribosomes, which are cars biomolecules that control protein synthesis. Disruption of ribosome function is a hallmark of many existing antibiotics, but some bacteria have developed protective mechanisms, shields, that prevent traditional drugs from working.

Cresomycin is one of several promising compounds Myers’ team is developing to help win the war against superbugs. Advances on these compounds are being achieved through preclinical profiling studies supported by a $1.2 million grant from the Biopharmaceutical Accelerator for Combating Antibiotic-Resistant Bacteria (CARB-X). CARB-X, a global non-profit association based at Boston University, is dedicated to supporting early-stage antibacterial drug research and development.

“Funding and other support from groups like the Blavatnik Biomedical Accelerator and CARB-X are essential for the discovery and development of new antibiotics,” said Curtis Keith, scientific director of the Harvard accelerator, in a statement. “These innovations from the Myers research group could potentially lead to the production of new drugs that one day meet global health needs.”

The Harvard team’s new molecule is inspired by the chemical structure of lincosamides, a class of antibiotics that includes the widely prescribed clindamycin. Like many antibiotics, clindamycin is produced by semisynthesis, in which complex products isolated from nature are directly modified for pharmacological use. However, Harvard’s new compound is entirely synthetic and represents chemical modifications that cannot be accessed through existing methods.

“The bacterial ribosome is nature’s preferred target for antibacterial agents. These agents are the inspiration for our program,” explains co-author Ben Tresco, a student at the Kenneth Griffin Graduate School of Arts and Sciences. “By harnessing the power of organic synthesis, we are almost limited only by our imagination when developing new antibiotics.”

How to develop new antibiotics that can bypass the resistance shield?

Bacteria create their shield, that is, resistance to antibiotics that target ribosomes, by expressing genes that produce enzymes called ribosomal RNA methyltransferases. They raise the wall to prevent drug components from entering the bacteria: they block drug components designed to stick to the ribosome.

To solve this problem, Myers and his team used what’s known as component-based synthesis, a method pioneered in the lab that involves making large molecular components of equal complexity and joining them together at a later stage in sections before creating the complex assembly. LEGO before assembling it. This modular synthetic system allows them to create and test one, if not hundreds of target molecules, greatly accelerating drug discovery.

Sara Hernando-Amado, a researcher specializing in the ecology and evolution of antibiotic resistance at the National Center for Biotechnology (CNB-CSIC), explains, as reported by SMC, that “an approach based solely on the development of new drugs will not solve the problem of antibiotic resistance. but the solution lies in the rational development of strategies that can limit the evolution of pathogenic bacteria.”

The CSIC researcher argues for this position. “Bacteria evolve unusually quickly, choosing adaptive mechanisms when they are under selective pressure. In fact, the same group many years ago described eravacyclinefor which resistance mechanisms have already been described in some pathogens.”

Although he notes that “in addition to producing new drugs, it is important to develop strategies that increase the sensitivity of bacteria to existing antibiotics and also avoid the selection of resistance. What we called temporary side sensitivity and which can be caused by Antibiotic-resistant clinical isolates of P. aeruginosa“.

In this sense, he clarifies that “the group of professor and founder of Tetraphase Pharmaceuticals Myers has extensive experience in the development of synthetic antibiotics. It is important to say that this new antibiotic, cresomycin, has activity against particularly dangerous ESKAPE pathogens, because Staphylococcus aureus or Pseudomonas aeruginosathe latter being an opportunistic pathogen causing approximately 600,000 deaths per year.”