New compound effective against drug-resistant pathogens

Researchers from North Carolina State University have synthesized an analog of lipoxazolidinone A, a small molecule that is effective against drug-resistant bacteria such as MRSA. This molecule, a new synthetic compound inspired by a natural product, could be a useful chemical tool for studying other Gram-positive infections and may have implications for future drug creation.

Lipoxazolidinone A is a natural product which had been previously isolated from bacteria living in marine sediments. It is a secondary metabolite -- a small molecule produced by the bacteria that isn't key to its survival but is produced for a secondary purpose, like defense. When lipoxazolidinone A was initially isolated, researchers noted that it seemed effective against Gram-positive bacteria, like MRSA.

NC State chemist Joshua Pierce aimed to confirm those original findings and understand how the molecule's structure correlated to its function; in short, he wanted to recreate the molecule to see what portions were directly responsible for its anti-microbial properties and then potentially improve upon that structure.

Pierce, along with current NC State graduate student Kaylib Robinson and former students Jonathan Mills and Troy Zehnder, used novel chemical tools to synthesize lipoxazolidinone A in the lab. They were able to confirm that its chemical structure matched what the initial researchers had indicated, then they worked to identify the portion of the molecule that was responsible for the activity against Gram-positive bacteria. Their result was a compound with improved potency, JJM-35.

They tested JJM-35 against a panel of resistant and non-resistant bacteria. When tested against MRSA in-vitro, they found that the synthesized molecule was up to 50 times more effective than the natural product against several bacterial strains. Additionally, they found that the molecule was often more effective against resistant bacterial strains than it was against nonresistant strains.

See:

Jonathan Mills, Kaylib Robinson, Troy Zehnder, Joshua G Pierce. Synthesis and Biological Evaluation of the Antimicrobial Natural Product Lipoxazolidinone A. Angewandte Chemie International Edition, 2018; DOI: 10.1002/anie.201805078

Posted by Dr. Tim Sandle