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New Synthetic Molecule Effective Against Superbugs

Computer-generated image of methicillin-resistant Staphylococcus aureus.
Credit: CDC/Unsplash
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A synthetic antibiotic molecule can kill drug-resistant strains of superbugs such as Staphylococcus aureus and Pseudomonas aeruginosa. The research, by Harvard University scientists, is published in Science.

This could help to tackle the issue of drug-resistant infections, which has been growing worldwide.

The battle against superbugs

Cresomycin is one of several promising compounds developed in the lab of Andrew Myers, senior author of the study and Amory Houghton Professor of Chemistry and Chemical Biology at Harvard. Their work is supported by a $1.2 million grant from the Combating Antibiotic-Resistant Bacteria Biopharmaceutical Accelerator (CARB-X), which supports early-stage antibacterial research and development.

“Antibiotics form the foundation on which modern medicine is built,” said Kelvin Wu, study co-author and graduate student at Harvard. “Without antibiotics, many cutting-edge medical procedures, like surgeries, cancer treatments and organ transplants, cannot be done.”

The new molecule draws inspiration from the chemical structures of a class of antibiotics called lincosamides.

These include drugs such as the commonly prescribed clindamycin, which is produced in a process called semisynthesis. This process uses complex products isolated from nature and modifiesthem for drug applications. The new Harvard-produced compound is 100% synthetic and features chemical modifications that cannot be accessed through existing means.

Cresomycin has an improved ability to bind to the biomolecular machines in bacteria that oversee protein synthesis, called ribosomes. Disrupting ribosome function is a tactic used by many existing antibiotics, but some bacteria can develop mechanisms to evade these functions and prevent drugs from working. Some bacteria begin to express genes that produce enzymes called ribosomal RNA methyltransferases that block the drug components.

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“The bacterial ribosome is nature’s preferred target for antibacterial agents, and these agents are the source of inspiration for our program,” said study co-author Ben Tresco, research assistant and graduate student in Myers’ lab. “By leveraging the power of organic synthesis, we are limited almost only by our imagination when designing new antibiotics.”

The compound was designed to have a rigid shape, giving it a stronger grip on the ribosome to prevent this resistance mechanism. The researchers describe the drug as being “pre-organized” for ribosomal binding as it doesn’t spend as much energy conforming to its target as existing drugs.

Potential new drugs to meet a global health challenge

Myers and colleagues discovered cresomycin using a method called component-based synthesis, pioneered by their lab. This process builds large molecular components of equal complexity and then assembles them in later stages of development. This can hugely speed up the drug discovery process, enabling them to make and test hundreds of target molecules.

“While we don’t yet know whether cresomycin and drugs like it 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 every year, compared with clinically approved antibiotics,” said Myers.

Reference: Wu KJY, Tresco BIC, Ramkissoon A, et al. An antibiotic preorganized for ribosomal binding overcomes antimicrobial resistance. Science. 2024;383(6684):721-726. doi: 10.1126/science.adk8013

This article is a rework of a press release issued by Harvard University. Material has been edited for length and content.