Our work has successfully realized the total synthesis of (−)-spiroaspertrione A, a highly promising candidate compound in the ongoing battle against drug-resistant bacteria. This achievement comes from a team led by Wenbo Huang and was detailed in a recent study published in the journal Science, with the DOI: 10.1126/science.adz7593. In 2017, researchers isolated this complex polycyclic compound from the fungal endophyte Aspergillus sp. Development of its synthesis—itself a complex process—could be another new weapon in the fight against the increasing threat posed by methicillin-resistant Staphylococcus aureus (MRSA).
(−)-spiroaspertrione A idiosyncratically increases permeability to otherwise impermeant antibiotics, potentially resensitizing MRSA to many of their previously ineffective therapeutic agents. The need for progress has never been more urgent. In 2021 MRSA infections were responsible for an estimated 130,000 deaths worldwide. This groundbreaking research further underscores the promise of (−)-spiroaspertrione A as a potent new antimicrobial compound. It serves as a centerpiece to unveil a new molecular strategy for synthesizing complex natural products.
The Synthesis Process
This total synthesis provided researchers with practical access to (−)-spiroaspertrione A. This complex process was realized through 16 careful steps, beginning with the chiral pool building block, (+)-enoxolone. Available at a cost below one euro per gram, this precursor was key for making the whole synthesis economically viable.
Using a highly adaptable aesthetic to overcome the complex structural challenges, researchers recently synthesized (−)-spiroaspertrione A. They employed a Diels–Alder cycloaddition strategy, succeeded by a key divinylcyclopropane rearrangement (DVCPR). It was a creative and outside-the-box approach that their team developed. Rather than adding to an already crowded molecular structure with heavier groups, they developed a versatile precursor molecule. For that to happen, we needed to heat the precursor up to 180°C, which caused a rather large molecular rearrangement. This bearing ring-closing reaction with a base produced the final product.
The first total synthesis of (−)-spiroaspertrione A is nontrivial. Particularly since researchers ended up with a low yield of 2.3%, which they understand seems low but is historically high because the compound is novel in nature.
Implications for Antibiotic Resistance
The significance of (−)-spiroaspertrione A goes beyond its synthesis. It is a strategic improvement in the fight against antibiotic resistance. Yet, as antibiotic-resistant infections increase at an alarming rate, new alternatives are more important than ever. If this compound is able to resensitize MRSA to drugs we already have, it will once again revolutionize treatment protocols and prevent the loss of millions of lives.
This urgent and unexpected MRSA epidemic has inspired an extensive search for effective alternative treatments. The synthetic proof-of-concept with (−)−spiroaspertrione A demonstrates the potential efficacy of such spirocyclic compounds. It’s an exciting artistic project, providing a scalable blueprint for its production is just as important. Huang and his team’s discoveries are groundbreaking. Their work will undoubtedly inspire the next groundbreaking research on natural products that are effective against resistant strains of bacteria.
Future Directions
Now that the synthesis of (−)-spiroaspertrione A has been accomplished, the research team is looking forward to future studies to unlock its complete therapeutic potential. Future studies will be needed to optimize the yield and identify derivatives that more effectively target resistant strains in order to bolster its efficacy.
Additionally, insight into the mechanisms of how this compound acts on bacterial cells will be key to establishing its position in clinical use. Scientists are optimistic that by studying (−)-spiroaspertrione A, we’ll be able to reap important lessons in the development of MRSA-fighting drugs. These findings will further lend themselves to nationwide efforts to improve the fight against antibiotic resistance.