Fighting bacterial infection by targeting the ability of pathogens to hijack the body's defense system

Bacteria such as Salmonella, E. coli or Shigella are among the deadliest pathogens in the world.
Understanding exactly how these life-threatening bacteria or pathogens operate and invade the host cells is essential to the search for novel antimicrobial therapeutics, especially considering the fundamental threat antibiotic resistance poses on global health. In that respect, recent research has opened up a promising avenue of investigation regarding the way bacteria manage to escape the body's defense system. It has indeed recently been established that specific bacterial enzymes, known as ubiquitin ligases, could hijack the host cells and subvert the cellular environment to their advantage by inhibiting the inflammatory response. However, the exact mechanisms by which these specific bacterial proteins achieve this regulation is largely unknown. Ultimately aiming to find potential targets for novel bacterial therapy, Dr. Maculins is investigating how these specific molecules are able to overturn some of the host cell's functions for their own benefit. Precisely, his focus is on understanding the mechanisms by which they manage to suppress the inflammatory response and assist bacteria to escape host defence.

"Throughout evolution, bacteria have acquired an intricate array of molecular armory that facilitates the hijacking of host cells", Dr. Timurs Maculins explains. "Recent studies demonstrate that upon entry in the host cells, pathogens inject a wave of effectors to the host cellular environment that hijack the host's signalling system to promote invasion and dissemination of bacteria".
"Among these effectors are molecules exhibiting the same activity as specific proteins of the human ubiquitin system", the researcher continues. "This is intriguing because bacteria don't have fully functional ubiquitin system." "In fact, what happens is that pathogens tend to copy the most important aspects of the human cells, that includes ligases of the ubiquitin system, and then replicate them for their own benefit". "Indeed, the ubiquitin system plays a central role in modulating signalling in human cells. It serves as a marker, a sort of beacon, which attach to other proteins and can affect their activity in various ways, including their immune and inflammatory response", Dr. Timurs Maculins points out. By aiming to obtain a detailed understanding of the role played by bacterial ubiquitin ligases in subverting signalling within the cell, the project's objective is to pave the way for the development of a new generation of antibacterials, this mechanism having never been targeted by pharmaceutical therapies in the past.

Towards developing a new generation of antibiotics that target bacterial ubiquitin ligases used to hijack the host cells

Dr. Timurs Maculins is conducting his two-year postdoctoral research at the Institute of Biochemistry II at the Goethe University of Frankfurt in the laboratory headed by Professor Ivan Dikic where a new and innovative detection approach of ubiquitinated proteins was recently developed. Applying this method to the study of Salmonella infection, the laboratory has already identified potential host targets of these bacterial ligases involved in innate immune response. The next step will be to unravel their exact functional significance upon Salmonella infection and translate these findings into pharmacological applications by identifying compounds capable of inhibiting the interaction between the bacterial ligases and their cognate targets in the host cell. In addition, the project will also investigate pathogenic Shigella and E. coli strains, looking to expand the possibilities of this application.

According to the World Health Organization, antibiotic resistance is considered to be one of the biggest threats to global health, food security and development. A growing number of infections are becoming harder to treat as the antibiotics used to treat them become less effective. Concretely, this translates into longer hospital stays, higher medical costs and increased mortality. By identifying bacterial ubiquitin ligases as novel drug targets for infectious diseases, Dr. Timurs Maculins' project offers promising perspectives for novel antibacterial therapeutical approach.

Fighting bacterial infection by targeting the ability of pathogens to hijack the body's defense system

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