Evolution and spread of drug resistance among bacterial pathogens

  • Project Leader

    Dr Kathryn Holt
    T: +61 03 9035 3155
    E: kholt@unimelb.edu.au
    W: Personal web page

    Location: Centre for Systems Genomics, Building 184 (Old Microbiology), Royal Pde, Parkville

Project Details

Before the introduction of penicillin in the 1940s, there was very little that could be done to treat bacterial infections, and so a huge number of people died every year from bacterial diseases including pneumonia, tuberculosis, wound infections, syphilis, and others. Penicillin and other antibiotics have since transformed these infections from lethal to treatable, and mortality associated with infections has dropped dramatically wherever antibiotics are widely used.

Unfortunately, while penicillin and other antibiotic compounds were 'new' to human knowledge in the 1940s, they were not new to the bacterial world (e.g. penicillin is produced naturally by particular types of fungi). As some bacteria have been exposed to penicillin for millennia in their natural environments, they have evolved a range of mechanisms to resist its bacteria-killing effects. The same is true for other antibiotics. Mechanisms of resistance include pumping the drug back out of the cell before it can do too much damage, breaking down the drug into harmless pieces, or modifying the bacteria's own proteins to prevent the drug from binding and causing problems.

These drug resistance mechanisms are all encoded in bacterial gene sequences, which can be passed around from one bacteria to the next via horizontal transfer. Unfortunately for us, it didn't take long for penicillin resistance genes to find their way from the environmental bacteria that were used to encountering penicillin, into the bacterial pathogens that cause the infections we would like to treat with the drug. The same is true for virtually every antibiotic drug available and there are now bacteria that can resist every drug we have, sometimes called 'superbugs'. This problem of multidrug resistance threatens to return us to the pre-antibiotic era, when bacterial infections were untreatable, and the WHO now considers it to be among the top 3 health problems facing humanity.

Because the evolution and spread of drug resistance is essentially a problem of gene transfer or mutation, it is most easily tracked and studied through DNA sequencing.

We use high-throughput platforms to sequence the complete genomes of drug-resistant and drug-susceptible bacterial pathogens, to investigate:

  1. how the resistance genes spread
  2. where and into which bacteria they spread
  3. how they impact the population structure of pathogens.

We have developed novel methods and tools to extract information about resistance genes and mutations direct from high-throughput sequencing data more quickly and accurately:

* Bandage – Bioinformatics Application for Navigating De novo Assembly Graphs Easily

Wick et al, Bioinformatics 2015

* ISMapper – Identifying insertion sequences in bacterial genomes from short read sequence data

Hawkey et al, BMC Genomics 2015

* SRST2 – Short Read Sequence Typing for Bacterial Pathogens (MLST, resistance gene typing, etc)

Inouye et al, Genome Medicine 2014

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Funding

This work is supported by a NHMRC project grant "Identifying key players in the spread of antimicrobial resistance" (APP1043830), which is a collaboration with Ruth Hall (University of Sydney), Mike Inouye (Dept Pathology) and Justin Zobel (Dept Computing and Information Systems).

Research Group

Holt laboratory: Pathogen genomics and bioinformatics



Faculty Research Themes

Infection and Immunology

School Research Themes

Infection & Immunity, Systems Biology



Key Contact

For further information about this research, please contact the research group leader.

Department / Centre

Biochemistry and Molecular Biology