Two-pronged approach to combat antibiotic resistance
Scientists from the US-based Wistar Institute have discovered a new class of compounds that combine direct antibiotic killing of pan drug-resistant bacterial pathogens with a simultaneous rapid immune response for combating antimicrobial resistance (AMR), publishing their findings in the journal Nature.
Existing antibiotics target essential bacterial functions, including nucleic acid and protein synthesis, building of the cell membrane and metabolic pathways. However, bacteria can acquire drug resistance by mutating the bacterial target the antibiotic is directed against, inactivating the drugs or pumping them out.
With this in mind, Wistar Institute researchers sought to identify a new generation of antimicrobials, named dual-acting immuno-antibiotics (DAIAs), taking what lead author Farokh Dotiwala described as “a creative, double-pronged strategy to develop new molecules that can kill difficult-to-treat infections while enhancing the natural host immune response”.
“We reasoned that harnessing the immune system to simultaneously attack bacteria on two different fronts makes it hard for them to develop resistance,” Assistant Professor Dotiwala said.
Asst Prof Dotiwala and colleagues focused on a metabolic pathway that is essential for most bacteria but absent in humans, making it an ideal target for antibiotic development. This pathway, called methyl-D-erythritol phosphate (MEP) or non-mevalonate pathway, is responsible for biosynthesis of isoprenoids — molecules required for cell survival in most pathogenic bacteria.
The researchers targeted the IspH enzyme, an essential enzyme in isoprenoid biosynthesis, as a way to block this pathway and kill the microbes. They then used computer modelling to screen several million commercially available compounds for their ability to bind with the enzyme, and selected the most potent ones that inhibited IspH function as starting points for drug discovery. Since previously available IspH inhibitors could not penetrate the bacterial cell wall, Asst Prof Dotiwala collaborated with Professor Joseph Salvino, a co-senior author on the study, to identify and synthesise novel IspH inhibitor molecules that were able to get inside the bacteria.
The team demonstrated that the IspH inhibitors stimulated the immune system with more potent bacterial killing 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 gram-positive bacteria. In preclinical models of gram-negative bacterial infection, the bactericidal effects of the IspH inhibitors outperformed traditional pan antibiotics. All compounds tested were shown to be nontoxic to human cells.
“We believe this innovative DAIA strategy may represent a potential landmark in the world’s fight against AMR, creating a synergy between the direct killing ability of antibiotics and the natural power of the immune system,” Asst Prof Dotiwala said. Indeed, given the broad presence of IspH in the bacterial world, the new approach may be able to target a wide range of bacteria.
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