New shape-shifting antibiotics inspired by military tanks show resistant to superbugs

Professor John E. Moses at Cold Spring Harbor Laboratory (CSHL) came up with the idea while observing tanks in military training exercises. The tanks were quick to respond to possible threats, thanks to rotating turrets. Based on his observations, Moses created an antibiotic that can shape-shift by rearranging its atoms, a new weapon against drug-resistant superbugs, stated a press release.

A new antibiotic with two vancomycin "warheads"

In his quest to find a super drug, Moses learned of a fluxional molecule called Bullvalene. This particular one's atoms can swap positions, allowing over a million possible configurations. Now, several bacteria, such as MRSA, VRSA, and VRE, have developed resistance to vancomycin, a potent antibiotic. Moses decided to combine the drug with bullvalene to increase its potential to fight bacteria.

For this, he turned to a chemical reaction called 'click chemistry.' "Click chemistry is great," Moses, who studied this revolutionary development under two-time Nobel laureate K. Barry Sharpless, said in a statement. "It gives you certainty and the best chance you’ve got of making complex things."

The high-yielding chemical reactions "click" molecules together, making the reactions more efficient for widespread use.

Moses and his colleagues then created a new antibiotic with "two vancomycin “warheads” and a fluctuating bullvalene center."

The researchers gave the new drug to VRE-infected wax moth larvae and found the shape-shifting antibiotic more effective than vancomycin at clearing the infection. Additionally, the bacteria didn’t develop resistance to the new antibiotic.

Moses explained that researchers can use techniques like click chemistry with shape-shifting antibiotics to create new drugs. "If we can invent molecules that mean the difference between life and death, that’d be the greatest achievement ever," he added.

The study is published in PNAS.

Study Abstract:

The alarming rise in superbugs that are resistant to drugs of last resort, including vancomycin-resistant enterococci and staphylococci, has become a significant global health hazard. Here, we report the click chemistry synthesis of an unprecedented class of shapeshifting vancomycin dimers (SVDs) that display potent activity against bacteria that are resistant to the parent drug, including the ESKAPE pathogens, vancomycin-resistant Enterococcus (VRE), methicillin-resistant Staphylococcus aureus (MRSA), as well as vancomycin-resistant S. aureus (VRSA). The shapeshifting modality of the dimers is powered by a triazole-linked bullvalene core, exploiting the dynamic covalent rearrangements of the fluxional carbon cage and creating ligands with the capacity to inhibit bacterial cell wall biosynthesis. The new shapeshifting antibiotics are not disadvantaged by the common mechanism of vancomycin resistance resulting from the alteration of the C-terminal dipeptide with the corresponding d-Ala-d-Lac depsipeptide. Further, evidence suggests that the shapeshifting ligands destabilize the complex formed between the flippase MurJ and lipid II, implying the potential for a new mode of action for polyvalent glycopeptides. The SVDs show little propensity for acquired resistance by enterococci, suggesting that this new class of shapeshifting antibiotic will display durable antimicrobial activity not prone to rapidly acquired clinical resistance.