Scientists at the Wistar Institute have discovered a new class of compounds that uniquely combine the direct killing of antibiotic-resistant bacterial pathogens, while at the same time providing a rapid immune response to fight antimicrobial resistance (AMR). These findings were published today in Nature.
The World Health Organization (WHO) has declared AMR one of the top 10 global health threats to humanity. It is estimated that by 2050, antibiotic-resistant infections could take 10 million lives each year and impose a cumulative burden of $ 100 trillion on the global economy. The list of bacteria that become resistant to treatment with all available antibiotic options is growing and few new drugs are being prepared, creating an urgent need for new classes of antibiotics to prevent public health crises.
“We have begun a creative two-pronged strategy to develop new molecules that can kill infections that are difficult to treat, while improving the host’s natural immune response,” said Farokh Dotiwala, Ph.D. MBBS, Assistant Professor of Vaccines and Immunotherapy Center and lead author of efforts to identify a new generation of antimicrobial agents called double-acting immuno-antibiotics (DAIA).
Existing antibiotics target basic bacterial functions, including nucleic acid and protein synthesis, cell membrane construction, and metabolic pathways. However, bacteria can acquire drug resistance by mutating the bacterial target to which the antibiotic is directed, deactivating the drugs, or pumping them out.
“We explained that slowing down their immune system to attack bacteria on two different fronts at the same time makes it harder for them to develop resistance,” Dotiwala said.
He and colleagues have focused on the metabolic pathway that is necessary for most bacteria, but is not present in humans, making it an ideal target for antibiotic development. This pathway, called methyl-D-erythritol phosphate (MEP) or the non-mevalonate pathway, is responsible for the biosynthesis of isoprenoids – molecules needed for cell survival in most pathogenic bacteria. The lab focused on the enzyme IspH, an essential enzyme in isoprenoid biosynthesis, as a way to block this pathway and kill microbes. Given the widespread presence of IspH in the bacterial world, this approach can target a wide range of bacteria.
The researchers used computer modeling to review several million commercially available compounds for their ability to bind to the enzyme and to select the most potent ones that inhibit IspH function as starting points for drug detection.
Because previously available IspH inhibitors could not penetrate the bacterial cell wall, Dotiwala collaborated with Wistar’s medical chemist Joseph Salvin, Ph.D., a professor at the Wistar Institute Cancer Center and co-senior author of the study, to identify and synthesize new IspH inhibitors. were able to enter inside the bacteria.
The team showed that IspH inhibitors stimulate the immune system with stronger bacterial 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 positive bacteria. In preclinical models of gram-negative bacterial infection, the bactericidal effects of IspH inhibitors outweighed traditional pan antibiotics. All compounds tested were shown to be non-toxic to human cells.
“Immune activation is the second line of attack for the DAIA strategy,” said Dr. Kumar Singh, a postdoctoral fellow from the Dotiwala laboratory and the first author of the study.
“We believe that this innovative DAIA strategy could represent a potential landmark in the global fight against AMR, creating a synergy between the ability to directly kill antibiotics and the natural strength of the immune system,” Dotiwala reiterated.
The work was supported by: the G. Harold and Leila Y. Mathers Foundation, funds from the Commonwealth Universal Research Enhancement (CURE) Program and the Wistar Science Discovery Fund; Pew Charitable Funds supported Farokh Dotiwala with a Wistar Institute employment grant; Additional support was provided by the Adelson Medical Research Foundation and the Department of Defense. Wistar Institute facilities were supported by a grant to support the Cancer Center P30 CA010815 and a grant from the National Institutes of Health S10 OD023586.
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