Edinburgh Infectious Diseases
EID logo 2019

Mechanisms in biology, evolution and physics underpinning AMR

Edinburgh has a significant depth of expertise addressing the fundamental biological and physical processes underlying the acquisition and spread of antimicrobial resistance.

Klebsiella pneumoniae (green) interacting with murine macrophages
Murine macrophages (red) interacting with gram negative Klebsiella pneumoniae (green).

Summary

Theme leader: Professor Rosalind Allen

Professor Rosalind Allen

Chair of Biological Physics

  • School of Physics and Astromony
  • College of Science and Engineering

Contact details

A strong interdisciplinary program of research on AMR involves scientists based in School of Physics (Institute for Condensed Matter and Complex Systems) who are combining experimental microbiology, physics and computational biology to investigate biofilms and the emergence of AMR.

Others based in the School of Biological Sciences and The Roslin Institute are investigating the mechanisms underpinning innate and acquired resistance to antimicrobials. Although the number of individuals working in this area is relatively small, the science is strong and innovative and benefits from recent major grant funding from the Wellcome Trust, ERC and China-UK Newton fund.

Highlights of research in this theme

How DNA damaging antibiotics can affect emergence of antimicrobial resistance

Project leader:  Meriem El Karoui, School of Biological Sciences

In all domains of life, cells rely on the correct replication and repair of their chromosomes to transmit genetic information. In bacteria, the importance of these processes is highlighted by the many clinically relevant antibiotics that cause DNA damage resulting in cell death but also in mutations leading to antibiotic resistance.

Bacteria can proliferate at very different speeds depending on their environment; some infections are very rapid whilst other will take much more time to develop. How fast bacteria grow affects all the molecular processes necessary for life, yet the connection between bacterial growth and sensitivity to DNA damaging agents has so far been overlooked. For example, it has been observed that slow growing bacteria are less sensitive to DNA damaging antibiotics, but the reasons underlying this observation are not known.

Combining experimental and theoretical methods, we aim to elucidate the molecular mechanisms that explain this important phenomenon and to quantify how it impacts the acquisition of drug resistance. Our ultimate goal is to discover new ways of manipulating bacterial growth for novel applications in antibiotic therapies.

This project is supported by ~£1m award from the Wellcome Trust.

DNA helix
How does DNA damage caused by antibiotics affect emergence of antimicrobial resistance?

How antibiotics affect bacterial physiology 

Project leader:  Rosalind Allen, School of Physics and Astronomy

Rosalind is interested in how antibiotics work, in the context of bacterial cell physiology. Her group approaches this question using a combination of laboratory model systems (eg growth rate measurements as a function of antibiotic concentration and growth environment) and mathematical models. Recently we showed, for example, that some ribosome-targeting antibiotics work better in a rich growth medium while others work better in a poor growth medium.

They are also interested in the mechanisms by which bacteria evolve resistance to antibiotics, especially in the context of spatial population growth such as biofilms.  They are combining laboratory models, computer simulations and mathematical calculations to address this problem.

This project is supported by £1.4m award from the European Research Council

Project leader:  Teuta Pilizota, School of Biological Sciences

Bacterial drug persistence is considered a major reason for failure of chronic infection treatments. All but a small fraction of cells will be killed when treated with an antibiotic.  The surviving cells (persisters) are genetically the same, therefore phenotypic variations in bacterial overall ‘health’ state are thought to lead to the occurrence of persisters.

Unlike resistant cells, persister cells suffer the damage from an antibiotic attack. However, their particular ‘health’ state in a given environment enables them to cope with the challenge and survive. Depending on the type of the attack the surviving strategy can vary. In order to understand how a given state of the cell leads to persister formation during an antibiotic attack, we are developing novel methods for single cell, real time measurements of changes in cellular health (such as internal pH and free energy availability) during treatment with antibiotics.

Based on the data we are aiming to understand the role of energetic state of the cell on persister formation. 

Spatial structure can have important effects on the genetic structure of populations
Spatial structure can have important effects on the genetic structure of populations

Evolution of antibiotic resistance

Project leader:  Luke McNally, School of Biological Sciences

Work in Luke's lab focuses on the evolution of antibiotic resistance within individual hosts. They are using a combination of mathematical modelling, experimental evolution and analysis of clinical data to address two key questions:

  1. Why is resistance easy to evolve for some drugs but more difficult for others?
  2. Can we optimise the sequence in which drugs are used to treat chronic infections in order to minimise cumulative resistance evolution?

Project leader:  Bartek Waclaw, School of Physics and Astronomy

Bartek is particularly interested in how the dynamics of microbial populations affect the acquisition of de novo mutations that confer resistance, and how such mutations spread in the population of bacteria. This process strongly depends on how bacterial cells are distributed in space, spatial distribution of the antibiotic, changes in the concentration of the antibiotic over time, and many others.  He is also interested in molecular mechanisms of action and resistance to different antibiotics, especially fluoroquinolones.  His work uses mathematical modelling and experiments, combining theory and simple, quantitative experiments to gain into the evolution of AMR.

Segregation of bacteria into domains
Modelling segregation of bacterial colony into domains.

Precision guided CRISPR/Cas9 bacteriophages for selective killing of AMR gut bacteria

Project leader:  Baojun Wang (School of Biological Sciences

In a project funded by the Gates Foundation, Baojun is aiming to engineer synthetic bacteriophages for highly selective and controlled killing of food-borne pathogens that are major causes of enteropathies in humans.  To achieve this, his group is engineering broad-host-range lysogenic phages that deliver sequence and strain-specific for selective cleavage of chromosomal target sites in gut colonising enteropathogenic bacteria.

Antimicrobial resistance in gram negative bacteria

Project leader:  Thamarai Schneiders, Division of Infection and Pathway Medicine

Antimicrobial resistance is an impending health crisis particularly in the treatment of gram-negative nosocomial bacteria.  Klebsiella pneumoniae is a significant pathogen that is rapidly becoming untreatable due to the spread of multidrug resistant organisms.

The success of pathogenic bacteria to survive under increasing antibiotic pressure can be attributed to both intrinsic and extrinsic mechanisms of resistance. Intrinsic mechanisms are generally not acquired and can be triggered as a first-line microbial response to antibiotic challenge.

Thamarai's laboratory has recently characterized intrinsic regulators such as RarA, RamA and their roles in conferring multi-drug resistance to last-line antimicrobial agents by modulating microbial permeability.  Given the rapid selectivity of these changes when exposed to any microbial stress, the overarching research aim iof her group is to elucidate how intrinsic systems facilitate microbial survival in the face of continued antibiotic and immune challenge.

Klebsiella on plate
The rise of antimicriobial resistance in gram-negative bacteria is one of the biggest challenges we face.