Shape-shifting antibiotic in study fights resistant infections

By Elissa Wolfson, The Science Advisory Board assistant editor

April 5, 2023 -- Researchers at Cold Spring Harbor Laboratory have created a new weapon against drug-resistant bacteria: an antibiotic that can shape-shift by rearranging its atoms.

The research, published Monday in the Proceedings of the National Academy of Sciences (PNAS), could help combat antibiotic resistance, deemed one of the top ten global public health threats by the World Health Organization (WHO).

In the U.S. alone, drug-resistant bacteria and fungi infect almost three million people per year and kill about 35,000. The recent overuse of several essential, effective antibiotics has led to bacteria developing resistance to them. Drug-resistant infections can be difficult, sometimes impossible, to treat. However, developing novel drugs and ensuring their safety for clinical use is a slow process. One alternative -- reengineering already-approved antibiotics to overcome resistance mechanisms -- takes advantage of established supply chains and clinical success, offering a quicker solution.

Vancomycin, a potent glycopeptide antibiotic which works by inhibiting the synthesis of a bacteria's cell walls, has long been used to treat bacterial infections including endocarditis, bone and joint infections, skin infections, bloodstream infections, colitis, and meningitis.

Considered a drug of last resort, vancomycin is also used in cases when other antibiotics are ineffective. However, several bacteria have now developed resistance to it, including vancomycin-resistant Enterococcus (VRE), methicillin-resistant Staphylococcus aureus (MRSA), and vancomycin-resistant Staphylococcus aureus (VRSA). Previous research has found that vancomycin dimers -- molecular structures consisting of two similar subunits -- displayed antibacterial activity superior to the parent drug against vancomycin-resistant bacteria.

The researchers learned of a fluxional molecule called bullvalene, which has atoms that can swap positions. This gives bullvalene a changing shape with over a million possible configurations -- precisely the fluidity they sought. They hypothesized that they could improve vancomycin's bacteria-fighting capabilities by combining vancomycin dimers with bullvalene.

They turned to click chemistry, a Nobel Prize-winning class of rapid, high-yielding chemical reactions that reliably click molecules together. This makes the reactions more efficient for wide-scale use and provides the best chance for making complex structures. Using this technique, the team created a new antibiotic with two vancomycin warheads and a fluctuating bullvalene center.

The researchers tested the new drug by giving it to VRE-infected wax moth larvae, which are commonly used to test antibiotics. They found that the shape-shifting antibiotic was significantly more effective than vancomycin alone at clearing the deadly VRE infection. Significantly, the bacteria didn't develop resistance to the new antibiotic. The researchers believe click chemistry may be used with other shape-shifting antibiotics to create a multitude of new drugs which may potentially be of great value to human health and survival.

"If we can invent molecules that mean the difference between life and death, that would be the greatest achievement ever," said co-author John Moses, professor of organic and click chemistry at Cold Spring Harbor Laboratory, in a statement.

Discovery of first steps in drug resistance process reveals new targets for antibiotics
Scientists have revealed the initial mechanisms that give rise to drug-resistant Escherichia coli, pointing to potential targets for antibiotics...
Multidrug-resistant bacteria cooperate to reduce the impact of antibiotics: study
Two of the most dangerous multidrug-resistant pathogens work together to nullify antibiotics, suggesting physicians need to determine if both bacteria...
Researchers discover new form of undetectable antimicrobial resistance
Australian researchers have discovered a new form of antimicrobial resistance that is undetectable using traditional testing methods. Their findings may...
Scientists develop new method to label proteins, track disease
Scientists at the Francis Crick Institute and Imperial College London have developed a new method to study the proteins released by cells, which could...
Nobel Prize in Chemistry awarded for click chemistry, which links molecules quickly
The Royal Swedish Academy of Sciences has awarded the 2022 Nobel Prize in Chemistry to three scientists for the development of click chemistry and bioorthogonal...
Molecule inhibits drug-resistant bacteria in mice with pneumonia, UTIs
A new molecule that inhibits drug-resistant bacteria in laboratory experiments, as well as in mice with pneumonia and urinary tract infections (UTIs),...
Programmable mRNA antibiotics show potential to combat antibiotic-resistant bacteria
Antibiotic-resistant bacterial strains are growing worldwide, with traditional antibiotics increasingly failing. However, programmable mRNA could be the...
Researchers fight drug-resistant bacteria with antibiotic 'Trojan horse'
In the latest chapter of the arms race between scientists and drug-resistant bacteria, scientists have devised an antibiotic-filled "Trojan horse" that...

Copyright © 2023 scienceboard.net


Conferences
Connect
Science Advisory Board on LinkedIn
Science Advisory Board on Facebook
Science Advisory Board on Twitter