The evolutionary arms race where bacteria evolve mechanisms to outsmart antibiotic drugs has left clinicians with a dearth of ways to fight bacterial infections effectively. To discover new antibiotics, researchers in chemist Andrew Myers’ laboratory at Harvard University turned to completely synthetic approaches. In their latest endeavors, they developed a completely synthetic antibiotic called cresomycin (1). This antibiotic, which binds to the bacterial ribosome, surmounts existing antimicrobial resistance mechanisms that have plagued current ribosome-binding antibiotics by being perfectly preconfigured to bind the ribosome tightly.
Many approaches to antibiotic discovery rely on naturally sourced compounds or use a semi-synthetic approach that modifies existing natural molecules. While semi-synthetic approaches can easily modify the periphery of the molecules, the more internal structures, such as the carbon-based framework, are more difficult to manipulate.
“It's my prediction that we might find that semi-synthesis will no longer be sufficient,” said Kelvin Wu, a graduate student in Myers’s group and coauthor of the paper. “We [will soon] have explored all the possible things or changes that we can make to the natural product.”
Having previously designed the synthetic antibiotic iboxamycin, the research team created a new antibiotic based on its structure and the structure of a related antibiotic, clindamycin (2). These antibiotics bind the bacterial ribosome and interfere with protein synthesis. The team noticed that when clindamycin and iboxamycin bound to the ribosome, they assumed an identical conformation. But before binding, these antibiotics have variable conformations; many of their bonds can rotate freely before moving into a specific conformation to bind the ribosome. A molecule that’s already pre-configured for binding could more effectively inhibit the ribosome since it requires less energy to achieve the correct conformation.
“We thought that we could freeze those rotatable bonds,” said Wu. “By fusing the rotatable bonds together, it cannot rotate anymore.” The team began with D-galactose as the starting material for synthesis, and after many chemical modifications, arrived at the structure of cresomycin.
“We took a leap of faith, so to speak, and tried to make something that hasn't been made before,” said Wu. When the team examined the crystal structure of cresomycin bound to the ribosome and in solution, they saw that the conformations were identical, indicating that the molecule was pre-organized for binding.
Wu and his colleagues found that cresomycin inhibits a variety of microorganisms, including ESKAPE pathogens that are multidrug resistant, in both in vitro experiments and in a mouse model.
We took a leap of faith, so to speak, and tried to make something that hasn't been made before.
- Kelvin Wu, Harvard University
“Being able to do total synthesis of the antibiotic from building blocks, as opposed to taking the original antibiotic and then doing chemical derivatives of it — that in itself is already a very interesting accomplishment,” said Axel Innis, a structural biologist at the European Institute of Chemistry and Biology who was not involved in the study. “It looks like a really good compound, and we'll have to see how it comes out in clinical trials.”
Myers recently received a CARB-X grant to pursue follow-up studies on cresomycin and other antibiotic candidates that the lab has created, including iboxamycin. The researchers will investigate the antibiotics’ oral bioavailability, toxicity, stability, and solubility.
“It's very much about the basic research, but also how we can translate that ultimately for the better of humankind,” said Wu.
References
- Wu, K.J.Y. et al. An antibiotic preorganized for ribosomal binding overcomes antimicrobial resistance. Science 383, 721–726 (2024).
- Mitcheltree, M.J. et al. A synthetic antibiotic class overcoming bacterial multidrug resistance. Nature 599, 507–512 (2021).
