Close-up of cresomycin bound to the bacterial ribosome of Thermus thermophilus. Credit: Yury Polikanov/University of Illinois Chicago
Key points:
- A new compound was found to kill many strains of drug-resistant bacteria, including Staphylococcus aureus and Pseudomonas aeruginosa.
- The molecule is fully synthetic and features chemical modifications that cannot be accessed through existing means.
- The molecule demonstrates an improved ability to bind to bacterial ribosomes.
A new antibiotic created by Harvard researchers overcomes antimicrobial resistance mechanisms that have rendered many modern drugs ineffective and are driving a global public health crisis.
The new synthetic compound—cresomycin—was found to kill many strains of drug-resistant bacteria, including Staphylococcus aureus and Pseudomonas aeruginosa.The molecule demonstrates an improved ability to bind to bacterial ribosomes, which are biomolecular machines that control protein synthesis.
The molecule draws inspiration from the chemical structures of lincosamides, a class of antibiotics that includes the commonly prescribed clindamycin. Like many antibiotics, clindamycin is made via semisynthesis, in which complex products isolated from nature are modified directly for drug applications. The new Harvard compound, however, is fully synthetic and features chemical modifications that cannot be accessed through existing means.
Bacteria can develop resistance to ribosome-targeting antibiotic drugs by expressing genes that produce enzymes, called ribosomal RNA methyltransferases. These enzymes box out the drug components that are designed to latch onto and disrupt the ribosome, ultimately blocking the drug’s activity. To get around this problem, Andrew Myers and team engineered their compound into a rigidified shape that closely resembles its binding target, giving it a stronger grip on the ribosome. The researchers call their drug “pre-organized” for ribosomal binding because it doesn’t need to expend as much energy conforming to its target compared with existing 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 bringing them together at late stages—like pre-building sections of a complicated LEGO set before assembling them. This modular, completely synthetic system allows them to make and test not just one, but hundreds of target molecules, greatly speeding up the drug discovery process.
Cresomycin is one of several promising compounds that Myers’ team has developed, with the goal of helping win the war against superbugs. They’ll continue advancing these compounds through preclinical profiling studies, supported by a $1.2 million grant from Combating Antibiotic-Resistant Bacteria Biopharmaceutical Accelerator (CARB-X).