New Class Of Dual-Acting Antibiotics Active Against A Wide R
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Wistar Institute scientists have discovered a new class of compounds that uniquely combine direct antibiotic killing of pan drug-resistant bacterial pathogens with a simultaneous rapid immune response for combatting antimicrobial resistance (AMR). These findings were published on December 23, 2020, in Nature.

We took a creative, double-pronged strategy to develop new molecules that can kill difficult-to-treat infections while enhancing the natural host immune response,” said Farokh Dotiwala, M.B.B.S., Ph.D., assistant professor in the Vaccine & Immunotherapy Center and lead author of the effort to identify a new generation of antimicrobials named dual-acting immuno-antibiotics.

He and colleagues focused on a metabolic pathway that is essential for most bacteria but absent in humans, making it an ideal target for antibiotic development.This pathway molecules required for cell survival in most pathogenic bacteria. The lab targeted the IspH enzyme, as a way to block this pathway and kill the microbes.

Researchers used computer modeling to screen several million commercially available compounds for their ability to bind with the enzyme, and selected the most potent ones that inhibited IspH function as starting points for drug discovery.

The team demonstrated that the IspH inhibitors stimulated the immune system with more potent bacterial killing activity and specificity than current best-in-class antibiotics when tested in vitro on clinical isolates of antibiotic-resistant bacteria, including a wide range of pathogenic gram negative and gram positive bacteria. All compounds tested were shown to be nontoxic to human cells.

“We believe this innovative DAIA strategy may represent a potential landmark in the world’s fight against AMR, creating a synergy between the direct killing ability of antibiotics and the natural power of the immune system,” echoed Dotiwala.

Source:
https://www.nature.com/articles/s41586-020-03074-x
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