Scientists develop a new class of antibiotics against a wide range of bacteria

Scientists at The Wistar Institute have designed a new class of antibacterial compounds. It is a unique combination of direct antibiotic killing of pan-drug resistant pathogens and a simultaneous rapid immune response to combat antimicrobial resistance (AMR). The team argues that the dual-acting immunoantibiotic (DAIA) strategy could represent a “landmark” in the fight against AMR.

“We have taken a creative and two-sided strategy to develop new molecules that can kill infectious diseases that are difficult to treat while boosting the natural host immune response,” said vaccines and immunity. Farokh Dotiwala, MBBS and PhD, assistant professors and leads of the Center for Therapy, said.The author of the team’s work, it is reported in Nature, “IspH inhibitors kill Gram-negative bacteria and mobilize immune clearance.. “

The World Health Organization (WHO) has declared AMR to be one of the top 10 global public health threats to humanity, and by 2050, antibiotic-resistant infections will kill 10 million people each year. It is estimated that it could impose a cumulative burden of $ 100 trillion. About the world economy. The list of bacteria that are becoming resistant to treatment with all available antibiotic options is growing, and there are few new drugs in the pipeline, so a new class of antibiotics to prevent public health crises. Is an urgent need.

Existing antibiotics target important bacterial functions such as nucleic acid and protein synthesis, cell membrane construction, and metabolic pathways. However, bacteria can acquire drug resistance by mutating the target of the bacteria to which the antibiotic is directed, inactivating the drug, or excreting them. “We thought it would be difficult to develop resistance if we used the immune system to attack bacteria on two different fronts at the same time,” said Dotiwala.

The team focuses their research on metabolic pathways that are essential for most bacteria but not present in humans, making them ideal targets for antibiotic development. “We are focusing on the methyl-d-erythritol phosphate (MEP) pathway for isoprenoid biosynthesis, which is essential for the survival of most gram-negative bacteria and the phylum Apicomplexa (malaria parasite). But it doesn’t exist in humans or other metazoans, “the team writes. ..

The MEP (or non-mevalonate) pathway is involved in the biosynthesis of isoprenoids, the molecules required for cell survival of most pathogens. In the laboratory, we targeted the IspH enzyme, an enzyme essential for isoprenoid biosynthesis, as a way to block this pathway and kill microorganisms. Given the widespread presence of IspH in the bacterial world, this approach has the potential to target a wide range of bacteria.

Researchers used computer modeling to screen millions of commercially available compounds for their ability to bind enzymes and selected the most potent inhibitors of IspH function as a starting point for drug discovery. Because previously available IspH inhibitors could not penetrate the bacterial cell wall, Dotiwala worked with Dr. Joseph Salvino, a professor at the Wistar Institute Cancer Center and co-lead author of the study, to the new IspH. Inhibitor molecules have been identified and synthesized. I was able to get inside the bacteria.

The team demonstrated that IspH inhibitors stimulate the immune system with stronger bactericidal activity and specificity than current best-in-class antibiotics when tested in vitro in clinical isolates of antibiotic-resistant strains. did. Positive bacteria. In a preclinical model of Gram-negative bacterial infection, IspH inhibitors outperformed conventional pan-antibiotics. “Immune activation represents the second line of attack in the DAIA strategy,” said Dr. Kumar Singh, a postdoctoral fellow at the Dotiwala lab and lead author of the study.

The compounds tested have been shown to not only act specifically on IspH, but are also non-toxic to human cells. “Our DAIA prodrugs are bacterially permeable and more effective against some species of multidrug-resistant strains than today’s best-in-class antibiotics,” the team said.

Researchers further pointed out that the bacteria are likely not developing a mechanism of resistance to their DAIA mechanism of action. “Unlike naturally occurring antibiotics, IspH inhibitors have not been found in microorganisms, so in the case of β-lactamase and macrolide antibiotics, resistance mechanisms such as β-lactamase and macrolide esterase have evolved in particular. It’s unlikely that you’re a prodrug, “they wrote. “The family of antibiotics and antibacterial strategies reported here synergize direct antibiotic action with a rapid immune response … This dual mechanism of action, which is a unique feature of these compounds, is a drug. It may delay the emergence of resistance. “

“This innovative DAIA strategy represents a potential landmark in the global battle with AMR and has the potential to create a synergistic effect between the direct killing capacity of antibiotics and the natural forces of the immune system. I believe, “said Dotiwala.