Antibiotic Resistance

Background:

Before penicillin was discovered in 1941, there was no cure for pneumonia or gonorrhoea. Death from infection following childbirth or trauma was commonplace. The experience of most people in developed economies today, however, is that bacterial infections can be cured easily with a short course of antibiotics. Unfortunately, the way we use these powerful compounds threatens to undermine the successes we have achieved. Bacteria are extremely adaptable and responsive to change, able to rapidly transform (mutate) to overcome external threats to their survival. The widespread use of antibiotics in health care and agriculture has produced antibiotic resistant bacteria. As resistance can be rapidly passed from one bacterium to another, "super bugs" now exist that are resistant to many, if not all current antibiotics. The scope and scale of resistance to most classes of antimicrobials is alarming. The situation is particularly acute in health care facilities, where antibiotic resistant bacterial infections result in:

  • Increased wait times as a result of lengthened hospital stays, and hospital wards and facilities closed due to isolation of infected patients.
  • Increased cost for the health care system due to increased hospital stays, increased diagnostic tests and more expensive treatments.
  • Increased morbidity (illness) and mortality (death) for Canadians infected with antibiotic resistant organisms, especially among at-risk populations such as the very young, very old, immunosuppressed and chronically ill.

Antibiotics have been the biggest therapeutic success in history and continue to save millions of lives but most of the antibiotics produced by the pharmaceutical industry during the last 40 years, with the exception of the oxazolidinones, have been minor modifications of compounds to which bacteria have already developed resistance. Consequently bacteria have rapidly adapted to evade these new drugs.

It is now estimated that one out of nine patients admitted to hospital each year – 250,000 Canadians – develop hospital acquired infections and of these patients, 8,000 die. This is greater than the number of fatalities from traffic accidents, AIDS and breast cancer combined. Many of these infections are resistant to available antibiotics and compounding the problem are infections acquired in other health care settings such as residential and long term care facilities and increasingly in the community at large.

Novel Alternatives to Antibiotics Initiative

Antibiotic resistance has been a research priority of the CIHR Institute of Infection and Immunity (III) since its inception and a variety of strategic research initiatives have been launched to address this global health problem, including the Safe Food and Water initiative and the more recent Novel Alternatives to Antibiotics (NAA) initiative. The NAA Funding Opportunity was designed to augment the existing research funding available through the CIHR open competitions by attracting applications focused on novel approaches to antibiotic resistance, including research areas such as phage therapy or probiotics in which Canada had little or no research capacity. The Funding Opportunity, launched in partnership with 26 private and public sector partners resulted in the funding of seven Seed Grants, two Fellowships, one Proof of Principle Award, two Collaborative Health Research Projects and eight Emerging Team Grants for a total investment of more than $13 million. Several of the funded projects were in the previously underserved area of bacteriophage research.

Canada UK Partnership

As a consequence of the NAA initiative, a partnership was initiated with the UK. In July 2007, the Canadian High Commission in London hosted a series of meetings between III, the Wellcome Trust and the UK MRC to explore opportunities for international partnership. The result was a Canada/UK workshop, organised by the UK MRC, III, and the Canadian High Commission which took place in London on February 6th and 7th, 2008. More than 40 participants were invited with roughly half being from the UK and half from Canada. The purpose of the workshop was to bring together researchers with different perspectives on the problem of antibiotic resistance in order to address topics such as immune modulation, molecular determinants of resistance, clinical aspects, and systems biology approaches. The objective was to assess whether there would be genuine gains through facilitating the creation and support of UK/Canadian partnerships between researchers with complementary expertise and whether such collaborations would result in improved mechanisms to address the problem of antibiotic resistance. The full workshop report.

Canada UK Catalyst Grant

The enthusiasm generated at the workshop translated into the joint launch by the III and the UK MRC of a one year Catalyst Grant Funding opportunity in December 2008. The intent was to promote the development of UK-Canadian basic and translational research collaborations in the area of antibiotic resistance and to provide the funds necessary for strategy development in preparation for potential funding opportunities for larger scale consortium type in the future. The following two projects were successful in this competition.

The Application Development Grants funded through the Canada-UK Joint Health Research Program on Antibiotic Resistance
Canadian Principle Investigator UK Principle Investigator Project Title
CLARKE, Anthony
University of Guelph
DOWSON, Christopher
University of Warwick, UK
Bilateral bacterial cell wall
biosynthesis network
WRIGHT, Gerard
McMaster University
PIDDOCK, Laura
University of Birmingham, UK
Antibiotic Resistance Research Pipeline

Canada UK Consortium Grant Funding Opportunity

In follow up to the successful outcomes of the Catalyst Grant program, III and the UK MRC launched the Team Grant: Canada-UK Partnership on Antibiotics Resistance RFA in September 2010. Through this initiative the research strengths in both countries will be combined to provide true value-added collaborations that will advance our approach to antibiotic resistance along the translational pipeline from biomedical research to clinical practice. As a result of this partnership, two large teams/consortia have received funding through a four year combined investment of $4 million and £2 million.

Canada-UK Team in Novel Antibiotic Targets in Cell Wall Biogenesis:

  • A.J. Clarke
    University of Guelph
  • N. Strynadka
    UBC
  • E. Brown
    McMaster University
  • L. Burrows
    McMaster University
  • R.C. Levesque
    Université Laval
  • G.S. Besra
    University of Birmingham
  • C. Dowson
    University of Warwick
  • D.I. Roper
    University of Warwick
  • A.J. Lloyd
    University of Warwick
  • T.D.H. Bugg
    University Warwick
  • S.J. Foster
    University of Sheffield
  • W. Vollmer
    University of Newcastle

Canada-UK Team in Bacterial Resistance to Beta-Lactam Antibiotics:

  • G. Dmitrienko
    University of Waterloo
  • W. Lubell
    Université de Montréal
  • J. Pitout
    University of Calgary
  • N. Strynadka
    UBC
  • D. Pillai
    UofT
  • S. Siemann
    Laurentian University
  • T. Walsh
    Cardiff University
  • J. Spencer
    Bristol
  • C. Schofield
    Oxford
  • C. Fishwick
    Leeds
  • D. Low
    Mount Sinai Hospital
  • J. Lui
    University of Waterloo

Dr. Gary Dmitrienko of the University Waterloo, working with Professor Tim Walsh of the University of Cardiff (UK), is studying the hard-to-treat gram-negative bacterial infections, like E. coli NDM-1, that cause some hospital-acquired infections. The team is investigating the Gram-negative bacteria that are resistant to carbapenem, currently the most powerful beta-lactam antibiotic, in hopes of developing a new treatment for these infections. The team will design, make, and test molecules that will block carbapenem-resistance mechanisms like NDM-1 and therefore enable carpanenems to kill resistant Gram-negative bacteria. They will also monitor the spread, particularly in hospitals, of carbapenem-resistant bacteria to help identify the most important sub-types to target.

Dr. Anthony Clarke of the University of Guelph, working with Professor Chris Dowson of the University of Warwick (UK), will study bacterial cell walls in the search for new antimicrobial targets against which new drugs can be developed. The group is focusing on peptidoglycan, the key polymer that holds the bacterial cell wall together, in order to develop new targets and small molecule probes that will inhibit peptidoglycan production and help kill the bacterium. The team proposes to consolidate research capacity across the two countries by making use of the technical expertise at the PG Synthesis Facility, centered at the University of Warwick, and the High Throughput Screening facility, located at McMaster University.