The resistance of bacteria to drugs intended to combat them has become one of the main public health problems around the world and in 2019 alone it was the direct cause of 1.27 million deaths, according to the World Health Organization. Health (WHO), which warns of the need to develop new antimicrobials – including antibiotics, antivirals, antifungals and antiparasitics – which are medicines used to prevent and treat infectious diseases in humans, animals and plants.
Scientists at Harvard University (USA) have now designed an antibiotic that can act effectively against many drug-resistant infections and address the threat they pose to humanity. The team has been led by Andrew Myers, Amory Houghton Professor of Chemistry and Chemical Biology, and has published their findings in the journal Science, where they explain that cresomycin, the synthetic compound they have created, kills many strains of drug-resistant bacteria, including Staphylococcus aureus and Pseudomonas aeruginosa.
“Although we do not yet know whether cresomycin and similar drugs are safe and effective in humans, our results show significantly improved inhibitory activity against a long list of pathogenic bacterial strains that kill more than a million people each year, compared to clinically approved antibiotics,” Myers said.
The new molecule demonstrates an improved ability to bind to bacterial ribosomes, which are biomolecular machines that control protein synthesis. Disruption of ribosomal function is a hallmark of many existing antibiotics, but some bacteria have evolved protective mechanisms that prevent traditional drugs from working.
A new weapon to win the war against superbugs
Cresomycin is one of several promising compounds Myers’ team has developed with the goal of helping win the war against superbugs. Their work to create these compounds through preclinical profiling studies is supported by a $1.2 million grant from the Biopharmaceutical Accelerator to Combat Antibiotic-Resistant Bacteria (CARB-X). CARB-X, a global nonprofit association based at Boston University, is dedicated to supporting early-stage antibacterial research and development.
The Harvard team’s new molecule is inspired by the chemical structures of lincosamides, a class of antibiotics that includes clindamycin, a commonly used drug that, like many antibiotics, is made through semisynthesis, in which complex products obtained in the nature are directly modified to have pharmacological applications. In contrast, the new Harvard compound is completely synthetic and presents chemical modifications that cannot be accessed by existing means.
“The bacterial ribosome is nature’s preferred target for antibacterial agents, and these agents are the source of inspiration for our program,” explained co-author Ben Tresco, a student at the Kenneth C. Griffin Graduate School of Arts and Sciences. . “By harnessing the power of organic synthesis, we are almost only limited by our imagination when designing new antibiotics.”
“Cresomycin shows significantly improved inhibitory activity against a long list of pathogenic bacterial strains that kill more than a million people each year”
Bacteria can develop resistance to ribosome-targeting antibiotics by expressing genes that produce enzymes called ribosomal RNA methyltransferases. These enzymes block components of the drug that are designed to disrupt the ribosome. To avoid this, Myers and his team designed their compound with a rigid shape that provides a more powerful grip on the ribosome. The researchers call their drug “preorganized” for ribosomal binding because it does not need to consume as much energy to fit its target as available drugs.
The researchers arrived at cresomycin using what they call component-based synthesis, a method pioneered by the Myers lab that involves building large molecular components of equal complexity and putting them together in late stages, like pre-construction sections of a complicated Lego set before to assemble it. This system allows them to make and test not just one, but hundreds of target molecules, greatly accelerating the drug discovery process.
What is at stake is clear. “Antibiotics form the foundation on which modern medicine is built. Without antibiotics, many cutting-edge medical procedures, such as surgeries, cancer treatments, and organ transplants, cannot be performed,” concludes co-author and graduate student Kelvin Wu.
