Scripps Researchers Create New Classes Of Antibiotics
By C. Rajan, contributing writer
In two recent developments, researchers at The Scripps Research Institute, La Jolla, CA have reported work on new classes of antibiotics to fight drug-resistant bacteria.
In the first study, a team of researchers from McMaster University in Canada and The Scripps Research Institute discovered that an existing drug called lamotrigine was able to inhibit the assembly of ribosomes in bacteria, thus preventing bacteria from making proteins and surviving.
While many existing antibiotics work by attacking the bacterial ribosomes’ functions, this study has revealed a drug that can actually prevent the ribosomes from being created in the first place. This provides researchers an approach for creating a new class of antibiotics that can be chemical inhibitors of ribosome assembly.
“Ribosome-inhibiting antibiotics have been routinely used for more than 50 years to treat bacterial infections, but inhibitors of bacterial ribosome assembly have waited to be discovered,” said Dr. Eric Brown, principal investigator of the study and a professor of biochemistry and biomedical sciences at McMaster’s Michael G. DeGroote Institute for Infectious Disease Research.
“Such molecules would be an entirely new class of antibiotics, which would get around antibiotic resistance of many bacteria. We found lamotrigine works.”
Lamotrigine is sold by GSK as Lamictal and is an anticonvulsant drug used in the treatment of epilepsy and bipolar disorder.
The researchers were also able to identify the precise target for the drug within the bacteria, thus proving them a clear understanding of ribosome assembly and the way these chemicals can work therapeutically.
The research has been published in the journal eLife.
In another approach, scientists at The Scripps Research Institute have devised a new powerful antibiotic based on vancomycin, which is effective against vancomycin-resistant strains of MRSA and other disease-causing bacteria.
The new vancomycin analog is unique as it demonstrates two distinct modes of anti-microbial action, making it difficult for bacteria to develop resistance mechanisms against the drug.
“This is the prototype of analogues that once introduced will still be in clinical use a generation or maybe even two generations from now,” said Dr. Dale L. Boger, the Richard and Alice Cramer Professor of Chemistry at Scripps.
Vancomycin is a powerful and commonly used antibiotic which is effective against a wide range of bacteria, including methicillin-resistant Staphylococcus aureus (MRSA), a major cause of hospital-acquired infections. However, vancomycin resistance in certain classes of bacteria is increasing.
Dr. Boger and his team have focused on making improved analogs of vancomycin, as opposed to creating entirely new compounds. “Vancomycin has lasted in clinical use for more than 50 years, in part because it isn’t very vulnerable to antibiotic resistance,” Dr. Boger said. “Our thought has been that if we find a vancomycin analog that addresses this current source of resistance we’ll get another 50 years of use out of it.”
In this recent study, Dr. Boger’s team made a couple of critical structural modifications to vancomycin, which resulted in an incredibly potent molecule. The new vancomycin analog fought well against the usual vancomycin-sensitive bacteria as well as vancomycin-resistant MRSA and enterococcal bacteria in laboratory in vitro tests.
Boger and his colleagues are now working on optimizing the chemical synthesis process in order to prepare sufficient quantities for preclinical testing in animals.
This study is available online in the Journal of the American Chemical Society.