New Group of Antibiotics Active Against Various Bacteria

New class of antibiotics act by directly killing the pan drug-resistant bacterial pathogens with a simultaneous rapid immune response for fighting antimicrobial resistance (AMR). These finding were published in Nature, by Wistar Institute scientists.

"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).

‘IspH inhibitors stimulate the immune system with more potent bacterial killing activity and specificity compared to the existing antibiotics.’
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Current antibiotics target nucleic acid and protein synthesis, building of the cell membrane, and metabolic pathways. But, bacteria can acquire drug resistance by modifying the bacterial target or by inactivating the drugs or pumping them out.

"We reasoned that harnessing the immune system to simultaneously attack bacteria on two different fronts makes it hard for them to develop resistance," said Dotiwala.

He and colleagues focused on a metabolic pathway called methyl-D-erythritol phosphate (MEP) or non-mevalonate pathway, that is responsible for biosynthesis of isoprenoids.

Drug Resistance – Antibiotic or Antimicrobial Resistance
Drug resistance is often a problem in malaria, tuberculosis, HIV, sexually transmitted diseases and hospital acquired diseases. Judicious use of antibiotics can control the problem.

The lab targeted the IspH enzyme, an essential enzyme in isoprenoid biosynthesis, as a way to inhibit 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 various y available compounds for their ability to bind with the enzyme, and selected the most potent ones that inhibited IspH function.

As existing 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 know and prepare novel IspH inhibitor molecules that can 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 found to be better than traditional pan antibiotics. All compounds tested were shown to be nontoxic to human cells.

"Immune activation represents the second line of attack of the DAIA strategy," said Kumar Singh, Ph.D., Dotiwala lab postdoctoral fellow and first author of the study.

"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-Medindia