New discoveries from a well-known antibiotic may prove to be crucial in the fight against antibiotic resistance. Photo by masakazu sasaki on Unsplash
Chemists have accidentally stumbled across a promising new antibiotic with powerful activity against drug-resistant bacteria, a glimmer of hope in the fight against antibiotic resistance.
Antimicrobial resistance
…common antibiotics are becoming increasingly ineffective against bacterial infections.
Antimicrobial resistance (AMR) is a real and growing threat to modern medicine. The widespread misuse and overuse of antimicrobials have created a strong selective pressure, causing resistant microbes to survive exposure, multiply, and establish strains that are difficult or even impossible to treat. As a result, common antibiotics are becoming increasingly ineffective against bacterial infections. Without intervention, it is estimated that bacterial AMR could claim 1.91 million lives in 2050.
Despite this growing problem, the antimicrobial industry is struggling. Developing new antibiotics is very expensive and offers limited financial reward, since most of the easily discoverable antimicrobials have already been found, and those that do reach the market are kept as last resorts. With the lack of financial incentives, few pharmaceutical companies are investing in antibiotic research and only a small number of antibiotics are in development. Because of this, it is not surprising that no new classes of antibiotics have been discovered since the 1980s. Clearly, there is an urgent and unmet need for investment in antimicrobial research and development.
Discovery of premethylenomycin C lactone
The well-known antibiotic methylenomycin A was discovered over 50 years ago. It is made naturally by the soil-dwelling bacteria Streptomyces coelicolor and is widely used in medicine, due to its effectiveness against Gram-positive bacteria (one of the two broad categories for bacteria).
In 2002, scientists sequenced the entire genome of S. coelicolor. This was the largest sequenced bacterial genome at the time, containing around 4.27 million base pairs of DNA. The researchers predicted 7,825 genes, including many previously unknown enzymes (proteins which speed up chemical reactions). Further analysis of a linear piece of S. coelicolor’s DNA, called plasmid SCP1, identified the gene cluster involved in the production of methylenomycin A. Based on DNA sequence comparisons to similar bacteria, 13 proteins from this cluster were suggested to play roles in building methylenomycins, a process called biosynthesis.
Building on this, a recently published paper initially set out to map the steps of methylenomycin biosynthesis in S. coelicolor. This work was a collaboration between the University of Warwick and Monash University, Australia. Using a genetic approach, they switched off each of the biosynthetic enzymes encoded by the genes mmyD, mmyO, mmyF, and mmyE, and observed the effect on methylenomycin production. The outcomes of three gene deletions were consistent with their previously proposed roles in methylenomycin biosynthesis. The mmyE mutant, however, accumulated two previously undiscovered intermediates, premethylenomycin C and premethylenomycin C lactone.
…both premethylenomycin C and premethylenomycin C lactone were more powerful than the original antibiotic, methylenomycin A.
It was several years later that testing of these compounds revealed their antibiotic properties. Amazingly, both premethylenomycin C and premethylenomycin C lactone were more powerful than the original antibiotic, methylenomycin A. In fact, the latter was found to be around 100 times more active than methylenomycin A against all the Gram-positive bacteria tested. Only small concentrations were needed to inhibit bacterial growth, as determined by standard minimum inhibitory concentration (MIC) assays, which measure the lowest concentration required to prevent visible bacterial growth.
Importantly, premethylenomycin C lactone was effective against Staphylococcus aureus and Enterococcus faecium, bacteria which have acquired resistance to many types of antibiotics and are responsible for methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus (VRE) infections. Vancomycin resistance is becoming problematic in treating E. faecium infections, despite it being reserved as a last-line antibiotic. In the study, E. faecium showed no signs of resistance to premethylenomycin C lactone after 28 days of repeated exposure, unlike to vancomycin, which required an eightfold higher concentration to have the same effect. This shows that E. faecium does not easily develop resistance to the new compound.
While these results are encouraging, there is still work to do to assess its toxicity in mammalian cells, explore its mechanism of action, and understand how its structural features contribute to its increased potency and resilience to resistance compared to methylenomycin A. Collaborative work has already demonstrated an eight-step process to make premethylenomycin C lactone both cheaply and on a large scale. The team also created modified versions of the compound. Studying these structural analogues will help determine which modifications are beneficial for its use as an antibiotic. Together, these insights will help guide the design of improved compounds suitable for pre-clinical testing.
Implications for future antibiotic discovery
…the potential value of returning to known natural biosynthesis pathways and identifying and testing the intermediates as a way to discover new and effective antimicrobials
Premethylenomycin C lactone is a highly promising candidate for the development of new antibiotics against drug-resistant Gram-positive bacteria. Remarkably, this powerful compound was hiding in plain sight inside a well-studied bacterium. This work highlights the potential value of returning to known natural biosynthesis pathways and identifying and testing the intermediates as a way to discover new and effective antimicrobials, as well as the need for ongoing scientific curiosity and collaboration.

