Project background and description
As soon as new antimicrobial drugs are discovered and used in the clinic, pathogenic bacteria inevitably evolve resistance, driving an unsustainable cycle threatening the twentieth century's improvements to public health. Antibiotics revolutionized modern medicine, but previously curable infections once again threaten millions of lives. To tackle antimicrobial resistance, next generation combination therapies could exploit vulnerabilities in interdependent gene functions essential during infection and manipulate resistance evolution into a dead end. However, many genes and their networks of functional interdependencies remain uncharacterized in non-model pathogenic bacteria.
We combine genetic tools, bioactive small molecules, and computation into a systems chemical biology  approach to dissect the infection biology of Mycobacterium tuberculosis, the causative agent of the deadliest infectious disease, and Klebsiella pneumoniae, the cause of many hard-to-treat urinary tract infections. Small molecules complement genetics because they are easily applied to disparate cell types and species, trivially combined, and directly bridge the gap between implication of genes in disease and new therapeutics. Building on our successful development of a new chemical genetic method, PROSPECT, to discover small molecule inhibitors of new targets in M. tuberculosis , we aim to develop a curated chemical toolbox for specific perturbation of gene functions alone and in combination to understand the network biology of M. tuberculosis and K. pneumoniae during infection. This knowledge will ultimately enable rational design of next generation antibacterial therapies .
The potential interdisciplinary PhD project seeks to characterize networks of genetic functional interdependencies in non-model pathogenic bacteria. Based on consultation with the candidate and their interests, this work could focus on the development of new genetic and small molecule tools, the evolvability of gene functions and networks essential for infection, the exploration of new anti-resistance therapeutic strategies, or characterization of the molecular biology of novel gene products from pathogenic bacteria.
The project will provide opportunities to develop skills from bacterial genetics (potentially including CRIPSR-based tools [4, 5] and transposon mutagenesis), microbiology, infection biology, high-throughput compound and genetic screening, chemical biology, quantitative biology, computational chemistry, and machine learning (potentially including deep learning and AI). There is also potential for collaboration with multiple groups at the Crick and other institutions.
We are looking for candidates with a background in chemical biology or quantitative biology with an interest in infectious disease, microbiology, or systems biology. A background in chemistry or experience of computational approaches is a plus, but enthusiasm for developing these skills is essential.
1. Johnson, E.O. and Hung, D.T. (2019)
A point of inflection and reflection on systems chemical biology.
ACS Chemical Biology 14: 2497-2511. PubMed abstract
2. Johnson, E.O., LaVerriere, E., Office, E., Stanley, M., Meyer, E., Kawate, T., . . . Hung, D.T. (2019)
Large-scale chemical-genetics yields new M. tuberculosis inhibitor classes.
Nature 571: 72-78. PubMed abstract
3. Johnson, E.O., Office, E., Kawate, T., Orzechowski, M. and Hung, D.T. (2020)
Large-scale chemical-genetic strategy enables the design of antimicrobial combination chemotherapy in Mycobacteria.
ACS Infectious Diseases 6: 56-63. PubMed abstract
4. Rock, J.M., Hopkins, F.F., Chavez, A., Diallo, M., Chase, M.R., Gerrick, E.R., . . . Fortune, S.M. (2017)
Programmable transcriptional repression in mycobacteria using an orthogonal CRISPR interference platform.
Nat Microbiol 2: 16274. PubMed abstract
5. Wang, Y., Wang, S., Chen, W., Song, L., Zhang, Y., Shen, Z., . . . Ji, Q. (2018)
CRISPR-Cas9 and CRISPR-assisted cytidine deaminase enable precise and efficient genome editing in Klebsiella pneumoniae.
Applied and Environmental Microbiology 84: e01834-01818. PubMed abstract