New class of double-acting antibiotics active against a wide range of bacteria

Double-acting antibiotics block an essential pathway in bacteria and activate the adaptive immune response.

Scientists at the Wistar Institute have discovered a new class of compounds that uniquely combine antibiotic direct death of drug-resistant bacterial pathogens with a rapid and simultaneous immune response to combat antimicrobial resistance (AMR). These findings were published on December 23, 2020, in Nature.

The World Health Organization (WHO) has declared AMR as one of the top 10 threats to global public health against humanity. It is estimated that in 2050, antibiotic-resistant infections can claim 10 million lives each year and impose a cumulative burden of $ 100 trillion on the global economy. The list of bacteria that are becoming resistant to treatment with all the available antibiotic options is growing and few new drugs are in the pipeline, creating an urgent need for new classes of antibiotics to prevent public health crises.

“We have adopted a creative and dual strategy to develop new molecules that can kill difficult-to-treat infections while increasing the host’s natural immune response,” said Farokh Dotiwala, MBBS, Ph.D., assistant professor at Vaccine & Immunotherapy Center and lead author the effort to identify a new generation of antimicrobials called double-acting immuno-antibiotics (DAIAs).

Existing antibiotics target essential bacterial functions, including nucleic acid and protein synthesis, construction of the cell membrane and metabolic pathways. However, bacteria can acquire resistance to drugs by mutating the bacterial target against which the antibiotic is directed, inactivating the drugs or pumping them out.

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

He and his colleagues focused on a metabolic pathway that is essential for most bacteria, but absent in humans, making it an ideal target for the development of antibiotics. This pathway, called methyl-D-erythritol phosphate (MEP) or non-mevalonate pathway, is responsible for the biosynthesis of isoprenoids – molecules necessary for cell survival in most pathogenic bacteria. The laboratory targeted the IspH enzyme, an enzyme essential in isoprenoid biosynthesis, as a way to block this pathway and kill microbes. Given the wide presence of IspH in the bacterial world, this approach can target a wide range of bacteria.

The researchers used computer modeling to examine several million commercially available compounds for their ability to bind to the enzyme and selected the most potent ones that inhibited IspH’s function as starting points for drug discovery.

Since previously available IspH inhibitors were unable to penetrate the bacterial cell wall, Dotiwala collaborated with Wistar medicinal chemist Joseph Salvino, Ph.D., professor at The Wistar Institute Cancer Center and senior co-author of the study, to identify and synthesize new IspH inhibitory molecules that managed to enter the bacteria.

The team demonstrated that IspH inhibitors stimulated the immune system with more potent bacteria elimination activity and specificity than today’s best antibiotics in the class when tested in vitro on clinical isolates of antibiotic resistant bacteria, including a wide range of gram negative pathogenic and gram positive bacteria. In preclinical models of gram-negative bacterial infection, the bactericidal effects of the IspH inhibitors outweighed traditional pan antibiotics. All compounds tested were found to be non-toxic to human cells.

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

“We believe that this innovative DAIA strategy can represent a potential milestone in the worldwide fight against AMR, creating a synergy between the direct death capacity of antibiotics and the natural power of the immune system,” echoed Dotiwala.

Reference: “IspH inhibitors kill Gram-negative bacteria and mobilize immune clearance” 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, Hsin-Yao Tang, Maxim Totrov, Joel Cassel, Maureen E. Murphy, Rajasekharan Somasundaram, Meenhard Herlyn, Joseph M. Salvino and Farokh Dotiwala, December 23, 2020, Nature.
DOI: 10.1038 / s41586-020-03074-x

Publication of information: IspH inhibitors kill Gram-negative bacteria and mobilize immune clearance ”, Nature (2020). Online publication.

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, Rajaramkharan Somasund and Meenhard Herlyn of Wistar; and Maxim Totrov of Molsoft LLC.

Work supported by: G. Harold Foundation and Leila Y. Mathers, funds from the Commonwealth Universal Research Enhancement Program (CURE) and Wistar Science Discovery Fund; The Pew Charitable Trusts supported Farokh Dotiwala with a recruitment grant from the Wistar Institute; Additional support was provided by the Adelson Medical Research Foundation and the Department of Defense. Support for the Wistar Institute facilities was provided by the Cancer Center Support Grant P30 CA010815 and the National Institutes of Health instrument grant S10 OD023586.

The Wistar Institute is an international leader in biomedical research with expertise in cancer research and vaccine development. Founded in 1892 as the first independent, nonprofit biomedical research institute in the United States, Wistar has held the prestigious Cancer Center designation of the National Cancer Institute since 1972. The Institute actively works to ensure that research advances move from the laboratory to the clinic as fast as possible.