One Step Backward, One Huge Leap Forward for Antibiotic Discovery!

In the midst of our antibiotic crisis, many different approaches are being taken to find a solution. An extremely interesting one which I happened upon took a unique approach involving backtracking to a metabolic intermediate of a specific antibiotic, which proved to be significantly more effective in combating antibiotic-resistant bacteria.

Researchers at the University of Warwick worked with the antibiotic-producing bacterium Streptomyces coelicolor and discovered two late-stage intermediates in the biosynthesis of the well-known antibiotic compound Methylenomycin A. These intermediates, for reasons not yet fully understood, were found to be far more potent than the final product itself.

Image credits: Original paper (see footer)

The team used gene-deletion strategies and detailed analytical chemistry to isolate and characterize these intermediates. One key molecule (the precursor dubbed “pre-methylenomycin C lactone”) displayed antimicrobial activity over 100 times stronger than Methylenomycin A against drug-resistant Gram-positive bacteria.

CRISPR-cas9 (a gene modification tool) (image credits: Iota Sciences)

Clearly, this is a monumental discovery. Typically, natural product research focuses on the final antibiotic molecule; however in this case, the earlier version of the compound appears to be a far more important find. This opens our eyes to a major scientific fact that up until now has seemingly been either overlooked or under-researched. The final product of a metabolic cycle is not the only compound produced by that organism, and as such we shouldn't only focus on it, but also all compounds that come before it. Because of this research, a near-infinite amount of new potential antibiotics may have been uncovered. Along these lines, the authors suggest that by exploring pathways and their intermediates, rather than just the end-products, we may uncover novel antibiotics that were overlooked simply because they never accumulate in large amounts inside the producing organism.

This discovery also highlights the importance of biosynthetic logic: according to the researchers, the bacterium S. coelicolor likely evolved the pathway from producing the potent compound down to a weaker version for reasons still unclear; perhaps regulatory, ecological, or metabolic. This further reinforces the idea that nature’s “finished” molecules aren’t always the most powerful ones.

In conclusion, by looking backwards in a metabolic pathway, we may have found a more effective approach to aquiring antimicrobial candidates that could help fill the urgent pipeline gap in antibiotics. While future steps for this specific compound, such as assessing safety, mechanism of action, and potential for development, must still be taken, utilization of this technique may hold the answer to ending our antibiotic crisis, once and for all.

References: Discovery of Late Intermediates in Methylenomycin Biosynthesis Active against Drug-Resistant Gram-Positive Bacterial Pathogens