At a glance
Researchers have designed synthetic drugs that inhibit protein production in various bacteria. The new antibiotic has proven effective against drug-resistant bacterial strains in mice, but has not yet been tested in humans.
Antibiotic-resistant bacterial infections cause more than 1 million deaths worldwide each year. That number is expected to increase further in the coming decades unless new antibiotics are developed.
Many antibiotics work by binding to bacterial ribosomes and causing them to stop functioning. These are the molecular machines that build the proteins that cells need to function. Over the past few decades, bacteria have evolved various mechanisms to prevent antibiotics from blocking ribosomes. Genetic mutations often change the chemical structure of ribosomes, preventing them from binding antibiotics.
A research team led by Dr. Andrew Myers of Harvard University, in collaboration with Dr. Yuri Polikanov of the University of Illinois at Chicago, has been studying ways to fine-tune antibiotics to overcome bacterial resistance. In a new study partially funded by the NIH, they looked at an older class of antibiotics called lincosamides. Their results were published in the journal Science on February 16, 2024.
Lincosamide antibiotics are called semi-synthetic drugs because they are based on molecules that occur in nature. Using knowledge of the molecular structures of these antibiotics and how they bind to bacterial ribosomes, the research team developed a fully synthetic compound called cresomycin. They chose its building blocks to form the precise shape needed to anchor tightly to the ribosome.
The research team found that klesomycin acts on both Gram-positive and Gram-negative bacteria. The latter is particularly difficult to treat with existing antibiotics. It was also effective against bacterial strains resistant to other lincosamide antibiotics.
The research team used X-ray crystallography to investigate how cresomycin overcomes the two most common resistance mechanisms that defeat other antibiotics. They obtained a crystal structure of klesomycin in complex with two ribosomes modified with different antimicrobial resistance genes. The structure reveals slight adjustments between the new antibiotic and the ribosome that allow for tight binding.
The researchers then tested cresomycin in mice infected with antibiotic-resistant Staphylococcus aureus. When treated with the new drug, 10 out of 10 mice infected with lethal doses of antibiotic-resistant bacteria survived for seven days. In contrast, 9 out of 10 mice that did not receive the drug died within 2 days after infection. Cresomycin also inhibited bacterial growth in mice infected with antibiotic-resistant E. coli and Pseudomonas aeruginosa.
When tested in cultured human cells, klesomycin did not cause any noticeable damage. The researchers are now working with a nonprofit biotech accelerator to move the drug closer to clinical trials.
“We don't yet know whether klesomycin and its analogues are safe and effective in humans. However, our results demonstrate that compared to clinically approved antibiotics, 1 million “We show significantly improved inhibitory activity against a long list of pathogenic bacterial strains that kill more than 1,000 people,” Myers said.
—Written by Sharon Reynolds
References: Antibiotics pre-tailored for ribosome binding overcome antimicrobial resistance. Reference Wu KJY, Tresco BIC, Ramkissoon A, Aleksandrova EV, Syroegin EA, DNY, Liow P, Dittemore GA, Yu M, Testolin G, Mitcheltree MJ, Liu RY, Svetlov MS, Polikanov YS, Myers AG. Science. 2024 Feb 16;383(6684):721-726. doi: 10.1126/science.adk8013. Epub 2024 February 15th. PMID: 38359125.
Funding: NIH's National Institute of Allergy and Infectious Diseases (NIAID) and National Institute of General Medical Sciences (NIGMS). National Science Foundation; Illinois Start-up Fund; Singapore Agency for Science, Technology and Research. German Forschungsgemeinschaft.
