Wistar Institute scientists have designed a new class of antimicrobial compound, which, they claim, uniquely combines direct antibiotic killing of pan drug-resistant pathogenic bacteria, with a simultaneous rapid immune response for combating antimicrobial resistance (AMR). The team claims the dual-acting immuno-antibiotics (DAIA) strategy could represent a “landmark” in the fight against AMR.

“We took a creative, double-pronged strategy to develop new molecules that can kill difficult-to-treat infections while enhancing the natural host immune response,” said Farokh Dotiwala, MBBS, PhD, assistant professor in the Vaccine & Immunotherapy Center and lead author of the team’s work, which is reported in Nature, in a paper titled, “IspH inhibitors kill Gram-negative bacteria and mobilize immune clearance.”

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

Existing antibiotics target essential bacterial functions, including nucleic acid and protein synthesis, building the cell membrane, and metabolic pathways. However, bacteria can acquire drug resistance by mutating the bacterial target that the antibiotic is directed against, inactivating the drugs or pumping them out. “We reasoned that harnessing the immune system to simultaneously attack bacteria on two different fronts makes it hard for them to develop resistance,” said Dotiwala.

The team centered their studies on a metabolic pathway that is essential for most bacteria, but which is absent in humans, making it an ideal target for antibiotic development. “We focus on the methyl-d-erythritol phosphate (MEP) pathway for isoprenoid biosynthesis, which is essential for the survival of most Gram-negative bacteria and apicomplexans (malaria parasites) but is absent in humans and other metazoans,” the team wrote.

MEP—or non-mevalonate—pathway, is responsible for biosynthesis of isoprenoids, molecules that are required for cell survival in most pathogenic bacteria. The lab targeted the IspH enzyme, an essential enzyme in isoprenoid biosynthesis, as a way to block this pathway and kill the microbes. Given the broad presence of IspH in the bacterial world, this approach might target a wide range of bacteria.

Researchers used computer modeling to screen several million commercially available compounds for their ability to bind with the enzyme, and selected the most potent inhibitors of IspH function as starting points for drug discovery. Previously available IspH inhibitors could not penetrate the bacterial cell wall, so Dotiwala collaborated with Wistar’s medicinal chemist Joseph Salvino, PhD, professor in The Wistar Institute Cancer Center and a co-senior author on the study, to identify and synthesize 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. “Immune activation represents the second line of attack of the DAIA strategy,” said Kumar Singh, PhD, Dotiwala lab postdoctoral fellow and first author of the study.

Flourescence microscopy staining showing the effects of DAIA treatment on bacteria viability. [The Wistar Institute]
As well as acting specifically on IspH, the compounds tested were also shown to be nontoxic to human cells. “Our DAIA prodrugs are bacteria-permeable and are more effective against several species of multidrug-resistant bacteria than the current best-in-class antibiotics,” the team stated.

 

The researchers further pointed out that bacteria will likely not have developed resistance mechanisms to the mechanism of action of their DAIAs. “Unlike antibiotics derived from natural sources, no IspH inhibitors have been discovered in microorganisms, so it is less likely that resistance mechanisms—such as β-lactamases and macrolide esterases in the case of β-lactam and macrolide antibiotics—have evolved specifically against our prodrugs,” they wrote. “The family of antibiotics and the antimicrobial strategy that we report here synergize direct antibiotic action with rapid immune response … This dual mechanism of action, an inherent feature of these compounds, could delay the emergence of drug resistance.”

“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,” said Dotiwala.

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