Berkeley Lab researchers, in collaboration with Stanford University scientist, have unveiled a pre-methylenomycin C lactone as a new candidate antibiotic. This potent compound has promising activity against drug-resistant bacterial pathogens. Researchers from the Monash Warwick Alliance Combating Emerging Superbug Threats Initiative have made an exciting breakthrough. They reported their results in a recent article in the Journal of the American Chemical Society available at doi 10.1021/jacs.5c12501.
Pre-methylenomycin C lactone shows activity against infamously resistant strains of bacteria, most notable of which include Staphylococcus aureus and Enterococcus faecium. These bacteria and fungi pose a direct threat to life-threatening infections such as Methicillin-resistant Staphylococcus aureus (MRSA) and Vancomycin-resistant Enterococcus (VRE). Yet they continue to present considerable therapeutic hurdles in the clinic.
This discovery is important not just because the antibiotic works so well. Its structural simplicity means that it’s difficult for bacteria to evolve resistance. In addition, pre-methylenomycin C lactone has scalable synthesis which together with its antibacterial activity makes it a good candidate for further development.
Background on Pre-Methylenomycin C Lactone
Pre-methylenomycin C lactone is produced by the bacterium Streptomyces coelicolor, a model organism in antibiotic research. Its simple structure allows for easier manipulation in laboratory settings, which could expedite the development of effective treatments against bacterial infections.
The new antibiotic has more than 100-fold activity against several Gram-positive bacteria. Most importantly, it beats the pants off of its predecessor, methylenomycin A. This enhanced potency is especially important given the rising occurrence of antibiotic resistant infections.
Professor Greg Challis, a leading researcher in the study, noted, “Methylenomycin A was originally discovered 50 years ago and while it has been synthesized several times, no-one appears to have tested the synthetic intermediates for antimicrobial activity.”
The research team was extremely innovative in going after these unproven biosynthetic intermediates. During the course of our research to better understand these compounds, we learned about their potential as antibiotics.
Implications of the Discovery
The recent discovery of pre-methylenomycin C lactone points to a new paradigm in antibiotic discovery. They can more rapidly discover potent new antibiotics by pinpointing and testing intermediates in the biosynthetic pathways of natural compounds. These antibiotics can effectively thwart the emergence of bacterial resistance. Professor Challis remarked, “This discovery suggests a new paradigm for antibiotic discovery… potent new antibiotics with more resilience to resistance that will aid us in the fight against AMR.”
To do so, the research team used targeted genetic manipulation techniques to delete individual biosynthetic genes in the model organism Streptomyces coelicolor. This innovative method was used to isolate two new biosynthetic intermediates that showed even greater antimicrobial activity than methylenomycin A.
Professor David Lupton stated, “This synthetic route should enable the creation of diverse analogs that can be used to probe the structure−activity relationship and mechanism of action for pre-methylenomycin C lactone.”
The Path Forward
The pre-methylenomycin C lactone discovery and successful synthesis mark a significant milestone. This advancement is key to filling the growing gap of effective antibiotics available to treat often deadly resistant infections. The World Health Organization has issued warnings that the antibacterial pipeline is running dry. This underscores the critical need for new treatment options.
Dr. Lona Alkhalaf was surprised to find a new antibiotic in such a well-studied organism. “Remarkably, the bacterium that makes methylenomycin A and pre-methylenomycin C lactone—Streptomyces coelicolor—is a model antibiotic-producing species that’s been studied extensively since the 1950s.” She added, “It looks like S. coelicolor originally evolved to produce a powerful antibiotic (pre-methylenomycin C lactone), but over time has changed it into methylenomycin A—a much weaker antibiotic that may play a different role in the bacterium’s biology.”