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Dr Christian Rudolph
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Research area(s)

− Molecular cell biology and bacterial chromosome dynamics

− DNA replication, replication stress and genome stability in Escherichia coli

− CRISPR-Cas systems and their interplay with DNA replication and DNA repair

− Replication–transcription conflicts and replication restart pathways

− Investigations of DNA replication dynamics in living bacterial cells

− The role of replication-associated processes in shaping bacterial chromosome architecture

Research Interests

The Rudolph Lab is involved in a variety of active research areas centred around DNA replication, replication stress and genome stability, and how these processes influence chromosome dynamics and bacterial chromosome architecture. Current projects in the laboratory include:

− We investigate DNA replication dynamics in Escherichia coli with a particular focus on DNA replication termination. We demonstrated for the first time that the RecG helicase can process DNA intermediates formed when replication complexes fuse. Our recent findings demonstrate that multiple proteins contribute to the processing of replication termination intermediates, thereby preventing severe defects in cell-cycle progression and genome stability. Importantly, our work demonstrates that termination is a threat to genomic stability even in wild type cells in which all DNA replication and repair factors are present. In addition, termination results in a global increase in the accumulation of R-loops. R-loops can interfere with DNA replication and therefore also threaten genomic stability. Further information can be found here. 

− We investigate replication–transcription conflicts at the single-molecule level in collaboration with Prof. Mark Leake (University of York).

− In collaboration with Prof. Ed Bolt (University of Nottingham), we investigate the interplay between CRISPR-Cas systems, DNA replication and genome stability. One particular question is how bacterial cells can distinguish invader chromosomes from their own genomic material. 

− We further investigate how replication-associated processes contribute to shaping the large-scale organisation and architecture of bacterial chromosomes.

Research in my laboratory has been supported by the Leverhulme Trust, the Royal Society, BBSRC and Brunel University London. Current work in the laboratory is supported by funding from the MRC.

Research grants and projects

Grants

Uncovering the antimicrobial and antibiotic potentiating mechanism of acesulfame-K and maximising its topical therapeutic potential
Funder: Medical Research Council
Duration: September 2023 - September 2026

Infectious diseases were once the leading cause of death amongst men and women in almost all age demographics in the UK. However, the discovery of antibiotics revolutionised our ability to treat bacterial infections and, as a result, saved millions of lives. Bacteria inhabit almost every corner of our planet due to their incredible ability to adapt to different environmental niches. This capacity to evolve and survive even in the most inhospitable environments means that, following the introduction of a new antibiotic to our healthcare systems, resistant bacterial strains rapidly appear. This cycle has kept repeating until the emergence, in some instances, of infections that cannot be effectively treated with any currently available antibiotics. This is creating a dangerous situation where a "post-antibiotic" era is now becoming a reality, threatening all aspects of healthcare from cancer treatment to dental work. At the forefront of pathogens that can evolve multidrug resistance is Acinetobacter baumannii. This pathogen can infect individuals who are already sick or have a supressed immune system, leading to a variety of life-threatening clinical complications and, potentially, death. This creates a problem particularly in hospitals where most A. baumannii outbreaks occur. Prior to the 2000s, A. baumannii infections were relatively infrequent and, typically, very treatable. However, there has been a rapid increase in the number of these infections, such that this bacterium now accounts for 20% of all infections seen in Intensive Care Units (ICUs) worldwide. These infections are incredibly difficult to treat, with up to 75% of A. baumannii isolated from these patients being resistant to more than 3 types of antibiotic. Previously, we have shown that the artificial sweetener acesulfame K (ace-K), a compound is consumed by millions of people around the world every day in "sugar free" or "calorie free" food and drinks, has a remarkable ability to tackle this pathogen. We demonstrated that not only can ace-K inhibit this pathogens growth. It can also inhibit a range of virulent processes that it uses to establish infection, including the ability to move from the initial site of infection and the capacity of this bacteria to form communities called biofilms which help it overcome antibiotic therapy. Remarkably, we also demonstrated that this compound will make A. baumannii vulnerable to antibiotics that it has previously evolved resistance to. We now want to explore what exactly ace-K is doing to the cell to stop it growing and to increase its sensitivity to antibiotics. We will use a range of cutting-edge fluorescent microscopy, proteomics and molecular biology techniques to uncover exactly how ace-k effects the bacterial cell and resensitises it to antibiotics. We will develop, characterise and assess novel ace-K loaded wound dressings to tackle acute and long-term, difficult to treat infections and test them in a porcine ex vivo wound model. We will also test these loaded wound dressings in a mouse wound model to determine their capacity to treat infection. As ace-k is approved for consumption by every international regulatory body including the Food and Drug Administration, it means it has been extensively tested for safety. Therefore, there is significant potential that the use of ace-K as a therapeutic to tackle infection could be fast tracked to clinical trials and into hospitals. This would overcome one of the main barriers delaying the introduction of new antimicrobials drugs which is that all the safety testing and trials required before final approval can take over 15 years on average to complete.

Nottingham Impact Bio-Accelerator Award
Funder: The University of Nottingham
Duration: June 2023 - October 2023

Seed funding to explore a potential new biotechnology/diagnostic application arising as an idea from recent CRISPR work

How bacteria replicate their DNA in spite of barriers one molecule at a time
Funder: Biotechnology & Biological Sciences Research Council
Duration: April 2022 - March 2025
Building CRISPR Immunity Systems - How is Invading DNA Captured?
Funder: Biotechnology & Biological Sciences Research Council
Duration: February 2020 - January 2023
Precision to the very end: what happens when two replication forks converge during termination?
Funder: Biotechnology and Biological Sciences Research Council
Duration: September 2016 - August 2019

Collaborative grant with York University

Project details

A major goal of the research in the Rudolph Laboratory is to understand how different forms of replication stress generate distinct DNA intermediates and how cells process these structures to preserve genome stability. Using bacterial systems as experimentally tractable model organisms, the laboratory investigates the molecular mechanisms that maintain chromosome integrity during DNA replication, repair and cell-cycle progression.

Currently the lab focusses on what might seem like a wide variety of topics, including the processing of replication termination intermediates, replication–transcription conflicts, replication restart pathways and the interplay between CRISPR-Cas systems, DNA replication and DNA repair, as well as how artificial sweeteners such as saccharin impact DNA replication in living cells. However, they all have DNA replication in common, and understanding DNA replication dynamics in living cells will be crucial to advancing all of these research areas. For this reason a particular emphasis is placed on understanding how stalled or disrupted replication forks are recognised and processed, and how these pathways contribute to chromosome organisation and long-term genomic stability and cell viability.

The laboratory combines molecular genetics, molecular cell biology and advanced microscopy approaches to investigate DNA replication dynamics in living bacterial cells. Our studies aim to establish broader mechanistic principles underlying chromosome maintenance and genome stability, with potential relevance for antimicrobial development and the understanding of genome instability-associated disease processes in eukaryotic cells.

Research links

Similar research interests

Research group(s)

  • IEHS