Friday, 8 January 2021

New class of antibiotics active against a wide range of bacteria



 


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 combating antimicrobial resistance (AMR).

Mirobiologists 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, called methyl-D-erythritol phosphate (MEP) or non-mevalonate pathway, is responsible for biosynthesis of isoprenoids -- molecules required for cell survival in most pathogenic bacteria. The lab targeted the IspH enzyme, an essential enzyme in isoprenoid biosynthesis, as a way to block this pathway and kill the microbes. Given the broad presence of IspH in the bacterial world, this approach may target a wide range of bacteria.

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.

Since previously available IspH inhibitors could not penetrate the bacterial cell wall, Dotiwala collaborated with Wistar's medicinal chemist Joseph Salvino, Ph.D., professor in The Wistar Institute Cancer Center and a co-senior author on the study, to identify and synthesize novel IspH inhibitor molecules that were able to get inside the bacteria.

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. In preclinical models of gram negative bacterial infection, the bactericidal effects of the IspH inhibitors outperformed traditional pan antibiotics. All compounds tested were shown to be nontoxic to human cells.


See:

Kumar Sachin Singh, Rishabh Sharma, Poli Adi Narayana Reddy, Prashanthi Vonteddu, Madeline Good, Anjana Sundarrajan, Hyeree Choi, Kar Muthumani, Andrew Kossenkov, Aaron R. Goldman, Hsin-Yao Tang, Maxim Totrov, Joel Cassel, Maureen E. Murphy, Rajasekharan Somasundaram, Meenhard Herlyn, Joseph M. Salvino, Farokh Dotiwala. IspH inhibitors kill Gram-negative bacteria and mobilize immune clearance. Nature, 2020; DOI: 10.1038/s41586-020-03074-x

 

 Posted by Dr. Tim Sandle, Pharmaceutical Microbiology Resources (http://www.pharmamicroresources.com/)

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