New Class of Antibiotics Active Against a Wide Range of Bacteria: Dual-Acting Immuno-Antibiotics
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"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 (DAIAs).
[...] [Dotiwala] 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, 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.
[...] 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.
Journal Reference:
Kumar Sachin Singh, Rishabh Sharma, Poli Adi Narayana Reddy, et al. IspH inhibitors kill Gram-negative bacteria and mobilize immune clearance, Nature (DOI: 10.1038/s41586-020-03074-x)
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