Dual-acting immunobiological antibiotics block essential bacterial pathways and trigger an adaptive immune response.

Wistar Institute scientists have discovered a new class of compounds that uniquely combine direct antibiotic killing of drug-resistant bacterial pathogens with a rapid immune response at the same time to combat resistance. (AMR). The discovery was published today in the journal Nature.

The World Health Organization (WHO) has declared AMR as one of the 10 global public health threats against humanity. It is estimated that by 2050, antibiotic-resistant infections could claim the lives of 10 million people each year and create a cumulative $100 trillion burden on the global economy. The list of bacteria that are becoming resistant to all currently available antibiotics is growing and several new drugs are being produced, creating a pressing need for new antibiotics to prevent public health crisis.

Farokh Dotiwala, MBBS, Ph.D., assistant professor in the Center for Immunization & Immunization and lead author of the effort to identify a new generation of antibiotics called dual-acting immunobiological antibiotics (DAIAs) ), said: “We have taken on an innovative dual strategy to develop new molecules that can destroy difficult-to-treat infections while enhancing the host’s natural immune response.”

Current antibiotics target the major functional activities of bacteria, including nucleic acid and protein synthesis, cell membrane construction, and metabolic pathways. However, bacteria can become resistant by altering the bacterial target the antibiotic is targeting, inactivating the drug, or releasing it.

“We reasoned that exploiting the immune system to attack bacteria on two different fronts makes it difficult for them to develop resistance,” says Dotiwala.

He and his colleagues focused on a metabolic pathway that is key for most bacteria but not in humans, making it an ideal target for antibiotic development. This pathway, known as the methyl-D-erythritol phosphate (MEP) or non-mevalonate pathway, is responsible for the biosynthesis of isoprenoids – molecules essential for cell survival in most pathogenic bacteria. . The lab targeted the enzyme IspH, an essential enzyme in isoprenoid biosynthesis, as a way to block this pathway and kill the bacteria. Due to the widespread presence of IspH in the bacterial world, this method can target a wide variety of bacteria.

The researchers used computer modeling to screen millions of commercially available compounds for their ability to bind to the enzyme and selected the most potent compounds that inhibit IspH function as the starting point for the study. medicine.

Because previously available IspH inhibitors were unable to penetrate bacterial cell walls, Dotiwala collaborated with Wistar pharmacologist Joseph Salvino, professor at the Wistar Institute Cancer Center and co-author of the study. research, to identify and synthesize new IspH inhibitor molecules that can penetrate inside bacteria.

The team demonstrated that IspH inhibitors stimulate the immune system with more specific and potent bactericidal activity than current best antibiotics when tested in vitro on resistant strains of bacteria. clinical isolates, including a wide range of pathogenic gram-negative and gram-positive bacteria. In preclinical models of gram-negative infections, the bactericidal effect of IspH inhibitors was superior to that of conventional antibiotics. All tested compounds have been shown to be non-toxic to human cells.

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

“We believe this innovative DAIA strategy could represent a potential turning point in the world’s fight against AMR, creating synergy between the drugs’ direct killing power,” emphasized Dotiwala. antibiotics and the natural strength of the immune system.”

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, Maureen E. Murphy, Rajasekharan Somasundaram , and Meenhard Herlyn from Wistar; and Maxim Totrov from Molsoft LLC.

The work was supported by: the G. Harold and Leila Y. Mathers Foundation, funds from the Commonwealth Universal Research Advancement (CURE) Program and the Wistar Science Discovery Fund; The Pew Foundation has supported Farokh Dotiwala with a Wistar Institute recruitment grant; Additional support is provided by the Adelson Medical Research Foundation and the Department of Defense. Support for the Wistar Institute facilities is provided by the P30 Cancer Center Support Grant.

Information sources:

Materials provided by The Wistar Institute. Note: Content may have been modified in presentation and length.

References:

1. IspH kill Gram-negative bacteria and mobilize immune clearance.

Kumar Sachin Singh, Rishabh Sharma, Poli Adi Narayana Reddy, Prashanthi Vonteddu, Madeline Good, Anjana Sundarrajan, Hyeree Choi, Kar Muthumani, Andrew Kossenkov, Aaron R. Goldman, Hsin-Yao Tang, Maxim Totrov, Joel Cassel, Maureen E. Murphy , Rajasekharan Somasundaram, Meenhard Herlyn, Joseph M. Salvino, Farokh Dotiwala. Nature, 2020;

DOI: https://www.nature.com/articles/s41586-020-03074-x

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Source: ScienceDaily

Link: https://www.sciencedaily.com/releases/2020/12/201223125759.htm

Author: Roxie Duong

Editing: Duong Ngoc