A group of compounds called IspH inhibitors are very potent against several multidrug-resistant Gram-negative bacteria, including those from the genera Acinetobacter, Pseudomonas, Klebsiella, Enterobacter, Vibrio, Shigella, Salmonella, Yersinia, Mycobacterium and Bacillus, and are elatively non-toxic to mammalian cells, according to new research from the Wistar Institute.

An artist’s impression of the multidrug-resistant bacteria Pseudomonas aeruginosa. Image credit: Jennifer Oosthuizen / Antibiotic Resistance Coordination and Strategy Unit, CDC.

An artist’s impression of the multidrug-resistant bacteria Pseudomonas aeruginosa. Image credit: Jennifer Oosthuizen / Antibiotic Resistance Coordination and Strategy Unit, CDC.

A metabolic pathway called methyl-D-erythritol phosphate pathway is essential for most bacteria but absent in humans, making it an ideal target for antibiotic development.

Also known as non-mevalonate pathway, it is responsible for biosynthesis of isoprenoids, molecules required for cell survival in most pathogenic bacteria.

IspH, an enzyme in the  pathway of isoprenoid synthesis, is essential for Gram-negative bacteria.

“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 co-senior author Dr. Farokh Dotiwala, a researcher in the Vaccine and Immunotherapy Center at the Wistar Institute.

Dr. Dotiwala and colleagues used computer modeling to screen several million commercially available compounds for their ability to bind with the IspH enzyme.

They 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, the researchers aimed to identify and synthesize novel IspH inhibitor molecules that were able to get inside the bacteria.

They 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.

In preclinical models of Gram-negative bacterial infection, the effect of the IspH inhibitors outperformed traditional pan antibiotics. All compounds tested were shown to be non-toxic to mammalian cells.

“Immune activation represents the second line of attack of the dual-acting immuno-antibiotic strategy,” said first author Dr. Kumar Singh, a postdoctoral researcher in the Vaccine and Immunotherapy Center at the Wistar Institute.

“We believe this innovative dual-acting immuno-antibiotic strategy may represent a potential landmark in the world’s fight against antimicrobial resistance, creating a synergy between the direct killing ability of antibiotics and the natural power of the immune system,” Dr. Dotiwala said.

The team’s results were published in the journal Nature.

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K.S. Singh et al. IspH inhibitors kill Gram-negative bacteria and mobilize immune clearance. Nature, published online December 23, 2020; doi: 10.1038/s41586-020-03074-x