Fighting antimicrobial resistance by signal jamming: interference with bacterial environment sensing mechanisms
Name of applicant
Clare Louise Kirkpatrick
Institution
University of Southern Denmark
Amount
DKK 4,230,318
Year
2021
Type of grant
Semper Ardens: Accelerate
What?
Bacteria sense, respond and adapt to the environment they are in. How they do so is still to a large degree unknown. This project focuses on the two-component system ChvIG, an environment sensing mechanism that is conserved between free-living and host-associated bacteria, including both beneficial plant symbiotes and plant, animal or human pathogens. In these cases, the system is important for sensing that the bacteria have contacted a host cell and for launching the gene expression programs needed for symbiosis or pathogenesis respectively. The aim of the project is to discover the precise factors that are sensed by the system, the downstream genes that are regulated by it, and develop pharmacological tools to tune signaling through the system, either positively or negatively.
Why?
Two-component systems are the first point of contact between a bacterium and its host cell, and signal transmission through them is vital for pathogenic bacteria to cause disease. ChvIG is extremely important for both positive and negative interactions between bacteria and their hosts, and this project will shed light on the currently unknown mechanisms by which it (a) senses the host-interaction environment and (b) alters the physiology of the bacteria accordingly. The knowledge and tools gained from studying ChvIG in our model system can be applied to future work on other two-component systems in pathogens and open new avenues for antimicrobial measures, using these systems as novel drug targets.
How?
We will use the non-pathogenic model organism Caulobacter crescentus as test system for (1) identifying and characterizing the genes regulated by the ChvIG system and (2) performing high throughput chemical-genetic screening to discover drugs or compounds which affect the cells differently depending on the presence or absence of ChvIG. Subsequently, we will investigate the function of homologous ChvIG target genes, and the effects of the compounds discovered through chemical-genetic screening, in the plant pathogen Agrobacterium tumefaciens and in the beneficial plant symbiont Sinorhizobium meliloti.