Understanding antibiotic resistance mechanisms in the world's pathogen of most concern: Acinetobacter baumannii

Secondary Supervisor(s): Professor Jess Blair

University of Registration: University of Birmingham

BBSRC Research Themes: Sustainable Agriculture and Food (Microbial Food Safety)

Project Outline

The “ESKAPE” pathogens, which evade most antibiotics, are a small group of bacteria, identified by the WHO in 2017, as presenting the greatest risk to global human health. Amongst these organisms, Acinetobacter baumannii, has been identified as the number one priority. The microbe thrives in hospitals, resists most antibiotics. It is thought that A. baumannii is so dangerous because it frequently rearranges its genome. This allows the organism to quickly evolve new characteristics and so avoid eradication.

My research group has recently discovered that A. baumannii has developed a molecular mechanism that allows it to "supercharge" its evolution (1). Put simply, the way in which DNA is organised inside A. baumannii cells determines how often different sets of genes are targeted for genetic change. To our knowledge, no similar process exists anywhere else in biology. At present, we are working with colleagues at the Queen Elizabeth Hospital in Birmingham to understand how the process we have discovered impacts disease caused by the bacterium. Similarly, we wish to understand how the process allows the microbe to survive for long periods in hospitals and avoid killing by antibiotics.

You will use a combination of genomic, genetic, molecular and biochemical tools. These will be applied to our current laboratory isolates of A. baumannii, and new isolates that we obtain from infected patients at the nearby Queen Elizabeth hospital. The ultimate goal is to understand the mechanisms by which genome rearrangements allow the bacterium to better infect the human host and persist in hospital environments.

References

1. Cooper C, Legood S, Wheat RL, Forrest D, Sharma P, Haycocks JRJ, Grainger DC (2024) H-NS is a bacterial transposon capture protein. Nat Commun. 15:7137.

Understanding the rules of life: how bacteria can "supercharge" their evolution

Secondary Supervisor(s): Professor Steve Busby

University of Registration: University of Birmingham

BBSRC Research Themes: Understanding the Rules of Life (Microbiology, Systems Biology)

Project Outline

My lab has discovered a process by which bacteria can “supercharge” their evolution (1). Specifically, transposable DNA sequences, so-called “jumping genes”, are directed to specific sites in chromosomes. Remarkably, sites targeted are those genes where genetic change is most beneficial. Since transposition is reversible, this allows rapid emergence and favourable traits without the risk of evolutionary dead-ends. Mechanistically, the process seems to be controlled by patterns of DNA folding inside cells. My hypothesis is that DNA folding is a major, and largely overlooked, regulator of bacterial evolution. I have only scratched the surface, and the consequences could be far reaching. Your project will take an integrated approach, across biological scales, to understand molecular mechanisms and their evolutionary consequences for all prokaryotes. You can expect to use techniques ranging from full genome approaches to focused molecular methods and computational tools.

References

1. Cooper C, Legood S, Wheat RL, Forrest D, Sharma P, Haycocks JRJ, Grainger DC (2024) H-NS is a bacterial transposon capture protein. Nat Commun. 15:7137.

Understanding how pandemic microbes evolve: Vibrio cholerae and the human disease cholera

Secondary Supervisor(s): Professor Steve Busby

University of Registration: University of Birmingham

BBSRC Research Themes: Sustainable Agriculture and Food (Microbial Food Safety)

Project Outline

Understanding the rules of species evolution is a fundamental question in biology. The emergence, spread and demise of harmful organisms, which can cause pandemics, is particularly important. You will focus on the bacterial species Vibrio cholerae. Recent advances in phylogenetics, model systems, and molecular tools, provide a timely opportunity to substantially progress our understanding. Your goal is to determine how evolution drives species development and pandemic potential. You will take a multi-level approach encompassing global species genetics, model ecosystems, and molecular mechanisms.

Currently, we cannot explain how the strain causing the current cholera pandemic arose, let alone predict why, where or when the next one might arise. The “success” of V. cholerae depends on its ability to adapt to different surroundings. Normally, the bacterium resides in aquatic environments and persists by forming biofilms on the chitinous surfaces of plankton and shellfish. These biofilms are rapidly disassembled on ingestion by a human or aquatic host. Following host colonisation, disease is caused by the extrusion of toxins (1). Hence, to understand what is special about the “pandemic” strain, it is essential to understand how the bacterium is able to switch between lifestyles. Recent work has generated a wealth of V. cholerae genome sequences (>10,000) from decades of outbreaks associated with the current worldwide pandemic (2,3). Our laboratory is using these data to try and understand key genetic changes that influence lifestyle choice and pandemic potential. Our work involves the application of bacterial genomics, molecular biology, and host organism colonisation models, to study lifestyle changes (4,5).

References

1. Nelson, EJ, Harris, JB, Morris, JG, Calderwood, SB, Camilli, A. (2009) Cholera transmission: the host, pathogen and bacteriophage dynamic. Nature Reviews Microbiology 7, 693-702.

2. Domman D, Quilici ML, Dorman MJ, Njamkepo E, Mutreja A, Mather AE et al. (2017) Science. Integrated view of Vibrio cholerae in the Americas. 358:789-793.

3. Weill FX, Domman D, Njamkepo E, Tarr C, Rauzier J, Fawal N et al. (2017) Genomic history of the seventh pandemic of cholera in Africa. Science. 358:785-789.

4. Manneh-Roussel J, Haycocks JRJ, Magán A, Perez-Soto N, Voelz K, Camilli A, Krachler AM, Grainger DC. (2018) cAMP Receptor Protein Controls Vibrio cholerae Gene Expression in Response to Host Colonization. mBio. 9:e00966-18.

5. Haycocks, JRJ, Warren, GZL, Walker, LM, Chlebek, JL, Dalia, TN, Dalia, AB, Grainger, D (2019) The quorum sensing transcription factor AphA directly regulates natural competence in Vibrio cholerae. PLoS Genet. 15:e1008362.

Ready, set, stop! Is bacterial transcription initiation coupled to termination?

Secondary Supervisor(s): Professor Ferenc Mueller

University of Registration: University of Birmingham

BBSRC Research Themes: Understanding the Rules of Life (Microbiology, Systems Biology)

Project Outline

DNA provides the information needed for life to exist. In all organisms, this information is divided into thousands of individual instructions called genes. Consequently, understanding how cells use their genes has far reaching implications. It is well-established that cells must first make a temporary copy of a gene, in the form of an RNA molecule, to access the encoded information. This copying process, called transcription, has fascinated me for the last 20 years. My laboratory studies the phenomenon in prokaryotic cells, accounting for the vast majority of life on Earth. In these organisms, transcription starts at parts of the DNA called promoters and stops at DNA loci called terminators. These start and stop signals have been considered separate entities since their discovery, many decades ago. My lab recently mapped all transcription start and stop sites in the DNA of multiple bacterial species (see reference below for some of this work). Remarkably, promoters and terminators are frequently coupled, sharing the same DNA sequence. The proposed project will build on this preliminary finding. You will determine the prevalence of coupled promoter-terminators across all prokaryotes, define the mechanistic basis, and understand the consequences for cells. Why is this important? Briefly, all aspects of cell behaviour depend on which genes are used at a given moment. I believe that coupled promoter-terminators represent a universal level of gene control that has long escaped our attention. There is great potential to influence many research areas. You can expect to use a range of techniques across the whole genome and molecular scales.

References

Warman EA, Forrest D, Guest T, Haycocks JJRJ, Wade JT, Grainger DC (2021) Widespread divergent transcription from bacterial and archaeal promoters is a consequence of DNA-sequence symmetry. Nat Microbiol. 6(6):746-756.