In the United States, nearly 3 million people are infected with drug-resistant bacteria and fungi each year, and about 35,000 die.multidrug resistance(multidrug-resistant, MDR) bacteria are one of the major global public health threats, requiring rapid delivery of new treatments to save patient lives. However, the development and clinical promotion of novel drugs is a slow process, and it is unlikely to solve this crisis in time. Researchers at Cold Spring Harbor Laboratory have found a new strategy to combat these super-resistant bacteria.Redesign clinically approved products using established supply chain and clinical resultsantibioticIn order to circumvent the resistance mechanism, it may provide a potential short-term solution.
The team’s findings have been published in theProceedings of the National Academy of Scienceswhich mentions a possible therapy to combat deadly infections with a new twist on antibiotics.
Inspired by the 2022 Nobel Prize “Click Chemistry” concept to accelerate the development process of new drugs
“Superbugs such as enterococci and staphylococci, which are resistant to vancomycin, have shown alarming increases and have become a serious global health hazard,” the researchers said. An unprecedented shapeshifting vancomycin dimers (SVD) synthesized by click chemistry. These dimers have strong activity against bacteria resistant to the parent drug, including ESKAPE pathogens, anti-pancomycin vancomycin-resistant Enterococcus (VRE), xylene-resistant Staphylococcus aureus (methicillin-resistant Staphylococcus aureus，MRSA) and vancomycin-resistant Staphylococcus aureus S aureus, VRSA) etc. “
who led the studyCold Spring Harbor LaboratoryProfessor John E. Moses, Ph.D., expressed the incredible potential of click chemistry and led him to study this revolutionary development under the supervision of two-time Nobel Laureate K. Barry Sharpless. Meanwhile, Dr. Moses came up with the idea for shape-shifting antibiotics while observing tanks during military training exercises. They found a molecule called a bullvalene, a fluid molecule whose atoms can swap places, giving it an ever-changing shape with more than a million possible configurations. Thus, the triazole-linked fenene core provides the dynamics for the dimer deformation mode, exploits the dynamic covalent rearrangement of the mobile carbon cage, and generates ligands with the ability to inhibit bacterial cell wall biosynthesis. The new shape-shifting antibiotics are not disadvantaged by the common mechanism of ubicomycin resistance due to alteration of the C-terminal dipeptide with the corresponding d-Ala-d-Lac desipeptide.
In addition, research evidence shows that deformed ligands destabilize the complex formed between flippase MurJ and lipid II, implying the potential of new modes of action for polyvalent glycopeptides . SVD showed little propensity to develop resistance against enterococci, suggesting that this new proteobacterial antibiotic would have long-lasting antimicrobial activity and be less prone to rapid clinical resistance.
Shape-shifting antibiotics may help overcome multidrug-resistant bacteria, and even become the key to species evolution
Dr. Moses’ research team administered the drug to wax moth larvae infected with panconmycin-resistant enterococci, which are commonly used to test antibiotics. They found that the proteobiotic was more effective than pancomycin at clearing up the deadly infection. In addition, the bacteria did not develop resistance to the new antibiotics. Researchers can use click chemistry and shape-shifting antibiotics to create a host of new drugs. This anti-infection weapon may even hold the key to the survival and evolution of the species. He said: “If we can invent molecules that determine life and death, it will be the greatest achievement ever.” The new discovery paves the way for further research on deforming antibiotic drugs and overcoming multi-drug resistant bacteria and pathogens.
Extended reading: Stop doing unnecessary resistance!New Antibiotic Could Cure Superbugs
References:
1. https://www.pnas.org/doi/10.1073/pnas.2208737120
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