Team:TU Eindhoven/Description
The Project
Inspiration
Bacterial infections such as urinary tract infections, wound and surgical site infections, which are quite common, are all treated with lots of antibiotics. An increasing problem nowadays, and one of the biggest threats to global health in thirty years, will be antimicrobial resistance (AMR). The pathogenic bacteria, that are causing infections, mutate and become resistant to the antibiotic arsenal used to treat these infections. A large recent study [1] on the burden of AMR in the EU and European Economic Area (EEA) estimated an increase from 239,238 age-adjusted infections with selected antibiotic-resistant bacteria in 2007 to 602,609 cases in 2015, with the median number of attributable deaths increasing from 11,144 to 27,249. The infamous methicillin-resistant S. Aureus (MRSA) accounts for a large fraction of the estimated 170 AMR DALYs (disability-adjusted life years) per 100,000 population, but also resistant strains of P. aeruginosa, K. pneumonia and E. coli already pose concerningly large effects on public health, with the third-generation cephalosporin-resistant E. coli causing 4.12 times as many fatalities in 2015 (8750) compared to 2007 [1]. Adding to the problem is the fact that no new classes of antibiotics have been developed in the last thirty years. If we do not intervene, AMR continues to grow which would mean that in 2050, 10 million people across Europe and the US alone will die because of AMR [2].
Description
We intend to reduce this threat by decreasing AMR and by exploring alternatives for antibiotics. A major accelerant of AMR is the misuse of antibiotics and the general application of very broad-spectrum antimicrobial agents, resulting in bacteria mutating and becoming immune to our once so powerful weapons. We aim to mitigate the AMR problem by improving the diagnostics of infections. By developing a more specific and faster detection method (Figure 1), we pave the way for infections to be treated more quickly and specifically without the development of antibiotic resistance. Fast detection is necessary during surgery, for example, to determine if an implant needs to be taken out. Specific detection is needed to administer specific types of antibiotics, instead of the very broad-spectrum ones. Moreover, our method could advance the application of another novel type of therapy: the use of bacteriophages to treat bacterial infections. As it happens, the detection of the specific bacterial pathogen at hand is based on the exquisite specificity of bacteriophages for their host bacteria. Upon infecting the host with its genomic DNA, the phage starts its replication process and for many types of lytic phages, within an hour the host cell is lysed and progeny phages and free phage DNA are released. This allows our dCas9-NanoLuc based bioluminescent sensors to bind the phage DNA and emit light, signaling the detection of phage specific DNA. In this way, this detection method could rapidly and specifically indicate the phage species the bacterial pathogen is susceptible to, thereby allowing the diagnosis of the bacterial species, providing a direction for the choice of antibiotic to treat with and directly opening a window for another potential treatment: the therapeutic use of said phage.
Moreover, the application of this method could be broad; from fast specific diagnosis of infections, both in human as well as in veterinary medicine, to the detection of bacteria in drinking water or in the food industry. The implementation of this fast and specific bacterial detection method will help ensure that we can keep on winning our fight against bacteria.
Figure 1: An overview of our method.
References
- Cassini, A.; Högberg, L. D.; Plachouras, D.; Quattrocchi, A.; Hoxha, A.; Simonsen, G. S.; Colomb-Cotinat, M.; Kretzschmar, M. E.; Devleesschauwer, B.; Cecchini, M.; et al. Attributable Deaths and Disability-Adjusted Life-Years Caused by Infections with Antibiotic-Resistant Bacteria in the EU and the European Economic Area in 2015: A Population-Level Modelling Analysis. Lancet Infect. Dis. 2019, 19 (1), 56–66.
- O’Neill, J. Review on Antimicrobial Resistance. Antimicrobial Resistan(1) O’Neill, J. Review on Antimicrobial Resistance. Antimicrobial Resistance: Tackling a Crisis for the Health and Wealth of Nations, 2014. 2014, 4 (December).Ce: Tackling a Crisis for the Health A. 2014, 4 (December).
