New technique identifies potential drugs to fight resistant bacteria

Washington, DC – June 20, 2021 – Researchers at the University of Miami in Ohio have optimized a new technique that will allow scientists to assess how potential inhibitors work on antibiotic-resistant bacteria. This technique, called native mass spectrometry, allows scientists to quickly identify the best candidates for effective clinical drugs, especially in cases where bacteria can no longer be treated with antibiotics alone. This research will be presented at the American Society for Microbiology’s World Microbe Forum online conference on June 21, 2021.

The abuse of antibiotics in the last century has led to an increase in bacterial resistance, leading to many bacterial infections that are no longer treatable with current antibiotics. In the United States, each year, 2.8 million people are diagnosed with a bacterial infection resistant to one or more antibiotics, and 35,000 people die from the resistant infection according to the Centers for Disease Control and Prevention.

“One method of combating antibiotic resistance is to use a drug / inhibitor combination,” said Caitlyn Thomas, Ph.D. candidate in chemistry, presenting author of the study. An example of this type of therapy is Augmentin, a prescription antibiotic used to treat bacterial infections of the respiratory tract, which is made up of the antibiotic amoxicillin and the inhibitor of clavulanic acid. Clavulanic acid inactivates a key protein that the bacteria use to become resistant to amoxicillin. Along with the bacterial protein inactivated, the antibiotic – amoxicillin – is left to kill the bacteria, thus treating the infection.

Before a new inhibitor can be used clinically, scientists must have a full understanding of how the inhibitor works. In the current study, Thomas and his team investigated a bacterial protein called metallo-beta-lactamase, which makes many clinical strains of bacteria resistant to all penicillin-type antibiotics. Penicillin-type antibiotics represent over 60% of the total antibiotic arsenal available to treat bacterial infections.

While many research laboratories around the world are trying to create new inhibitors that inactivate metallo-beta-lactamases, Thomas and colleagues are instead analyzing how these new inhibitors work. “Because metallo-beta-lactamases contain two metal ions, we are able to use a variety of spectroscopic techniques to study them,” Thomas said. “These experiments give us more information about how the inhibitor behaves and whether it could potentially be a candidate for clinical use in the future.”

Hundreds of potential inhibitors have been reported in the literature, and several patents have been filed relating to metallo-beta-lactamase inhibitors. Some of the reported inhibitors work by removing a required component of metallo-beta-lactamase. These same inhibitors can remove this same required component of other proteins in humans, causing serious side effects. Other inhibitors bind directly to metallo-beta-lactamase and inactivate the protein; inhibitors of this type are optimal for any new inhibitor that could be used clinically.

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This work was carried out by Caitlyn A. Thomas, Zishuo Cheng, John Paul Alao, Kundi Yang, Richard C. Page and Andrea N. Kravats under the supervision of Michael W. Crowder at the University of Miami, Oxford, OH and is funded by the NIH (GM134454).

World microbe forum is a collaboration between the American Society for Microbiology (ASM), the Federation of European Microbiological Societies (FEMS) and several other societies, which breaks down barriers to share science and address the most pressing challenges facing humanity today ‘hui confronted.

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