Dual-acting immune antibiotics block important pathways in bacteria and activate adaptive immune responses.
Scientists at the Wistar Institute have discovered a new compound that uniquely combines antibiotics that directly kill pandrug-resistant bacterial pathogens with simultaneous rapid immune responses to combat antimicrobial resistance (AMR). These findings were published on December 23, 2020, nature.
The World Health Organization (WHO) has declared AMR as one of the top ten public threats to humans in the world. It is estimated that by 2050, drug-resistant infections may kill 1
“We have adopted an innovative, two-pronged strategy to develop new molecules that can kill difficult-to-treat infections while enhancing the immune response of the natural host,” said MBBS PhD, Assistant Professor of Vaccines and Immunotherapy Farokh Dotiwala. The center and the lead author are dedicated to identifying a new generation of antimicrobial agents called dual-acting immunoantibiotics (DAIAs).
Existing antibiotics target the basic functions of bacteria, including nucleic acids acid As well as protein synthesis, cell membrane construction and metabolic pathways. However, bacteria can acquire drug resistance by mutating the bacterial target gene targeted by the antibiotic, inactivating the drug or pumping it out.
Dotiwala said: “We think that using the immune system to attack two different bacteria at the same time will make it difficult for bacteria to develop resistance.”
He and his colleagues focused on metabolic pathways that are essential to most bacteria but do not exist in humans, making them ideal targets for antibiotic development. This pathway is called the methyl D-erythritol phosphate (MEP) or non-mevalonate pathway and is responsible for the biosynthesis of isoprenoids-isoprenoids are responsible for cell survival in most pathogenic bacteria. Required molecule. The laboratory has conducted research on IspH enzyme, an essential enzyme in isoprenoid biosynthesis, to block this pathway and kill microorganisms. In view of the widespread existence of IspH in the bacterial kingdom, this method may target a variety of bacteria.
Researchers used computer modeling methods to screen millions of commercially available compounds for their ability to bind to enzymes, and selected compounds that inhibit the function of IspH most effectively as the starting point for drug discovery.
Because previously available IspH inhibitors cannot penetrate the bacterial cell wall, Dotiwala collaborated with Wistar’s medicinal chemist Dr. Joseph Wivin, a professor at the Wistar Institute Cancer Center, and the co-senior author of the study to identify and synthesize a new IspH. Inhibitor molecules that can enter bacteria.
The team proved that when tested in vitro on clinical isolates of antibiotic-resistant bacteria, IspH inhibitors have stronger bactericidal activity and specificity than current best-in-class antibiotics, thereby stimulating the immune system, including a variety of Pathogenic Gram-negative and Gram-negative bacteria. Positive bacteria. In preclinical models of gram-negative bacterial infections, the bactericidal effect of IspH inhibitors is better than traditional pan antibiotics. All tested compounds are shown to be non-toxic to human cells.
Dr. Kumar Singh, a postdoctoral researcher in the Dotiwala laboratory and the first author of the study, said: “Immune activation is the second line of attack in the DAIA strategy.
“We believe that this innovative DAIA strategy may represent a potential milestone in the world’s fight against AMR, creating a synergy between the direct killing ability of antibiotics and the natural forces of the immune system.”
References: References written by Kumar Sachin Singh, Rishabh Sharma, Poli Adi Narayana Reddy, Prashanthi Vonteddu, Madeline Good, Anjana Sundarrajan, Hyeree Choi, Kar Muthumani, Andrew Kossenkov, Aaron R. Goldman: “IspH inhibitor kills gram Negative bacteria and mobilize immune clearance”, Tang Xinyao, Maksim Totrov, Joel Kassel, Maureen Murphy, Rajasthan Somasundalan, Meinhard Herring , Joseph Salvino and Faro Dotivara, December 23, 2020, nature.
DOI: 10.1038 / s41586-020-03074-x
Publication information: IspH inhibitors can kill Gram-negative bacteria and mobilize immune clearance, “Nature” (2020). Online publishing.
Co-authors: Rishabh Sharma, Poli Adi Narayana Reddy, Prashanthi Vonteddu, Madeline Good, Anjana Sundarrajan, Hyeree Choi, Kar Muthumani, Andrew Kossenkov, Aaron R. Goldman, Hsin-Yao Tang, Joel Cassel, Maunden E. Murphy, Rajasekharan Somas, Rajaseran Meenhard Herlyn from Wistar; and Maxim Totrov from Molsoft LLC.
Work funded by the G. Harold and Leila Y. Mathers Foundation, Commonwealth Universal Research Enhancement (CURE) Program and Wistar Science Discovery Foundation; Pew Charitable Trusts supports Farokh through Wistar Institute recruitment grants Dotiwala; Adelson Medical Research Foundation and the Department of Defense provided additional support. Support for the Wistar Institute facility was provided by Cancer Center Support Grant P30 CA010815 and National Institutes of Health Instrument Grant S10 OD023586.
Wistar Institute is an international leader in biomedical research, with special expertise in cancer research and vaccine development. Founded in 1892, Wistar is the first independent non-profit biomedical research institute in the United States. Since 1972, it has been awarded the prestigious title of cancer center by the National Cancer Institute. The institute is actively committed to ensuring that research progress is quickly transferred from the laboratory to the clinic. As much as possible.