Design and development of antibiotics against multidrug resistant bacteria

Project Details

Polymyxins are cyclic heptapeptides with a tripeptide side chain linked to a fatty acid tail (Figure 1). They are polycations at physiological pH owing to the five L-a,g-diaminobutyric acid (Dab) residues. They have a narrow spectrum of activity which is mainly against Gram-negative bacteria. Currently, they are mainly used as last-line antibiotics for multidrug resistant (MDR) Gram-negative infections. Although the incidence of resistance to polymyxins is currently relatively low, resistance can emerge rapidly in vitro in P. aeruginosa, A. baumannii and K. pneumoniae, and polymyxin resistance in hospitalised patients has been increasingly reported.

Figure 1: Flow chart of novel safe octapeptins targeting XDR Gram-negative pathogens

Figure 1: Novel safe octapeptins targeting XDR Gram-negative pathogens

There is only one amino acid difference between colistin and polymyxin B and, not surprisingly, cross resistance exists. In essence, resistance to polymyxins implies a total lack of antibiotics for treatment of life-threatening infections caused by these MDR Gram-negative ‘superbugs’. Numerous hospitals worldwide have experienced outbreaks of infections caused by P. aeruginosa, A. baumannii or K. pneumoniae that are resistant to all commercially available antibiotics, including the last-line therapies colistin (polymyxin E) and polymyxin B. Infection with MDR Gram-negative pathogens is a major public health problem worldwide and as such there is an urgent need for new antibiotics active against MDR infections.

The principle aim(s) of this project include:

  1. Determine the mechanism of action of novel polymyxin antibiotics active against P. aeruginosa, A. baumannii and K. pneumoniae, in particular polymyxin-resistant strains.
  2. Assess the synthetic peptides against polymyxin-susceptible and -resistant strains, for (a) antibacterial activity, (b) potential for development of resistance, and (c) interactions with LPS.
  3. Investigate for highly active analogs their (a) stability in human plasma, (b) potential haemolytic effects, (c) pharmacokinetics and potential nephrotoxicity in animals, followed by (d) proof-of-concept studies using animal infection models.

Research Opportunities

This research project is available to Honours students, Master of Biomedical Science to join as part of their thesis.
Please contact the Research Group Leader to discuss your options.

Research Group

Tony Velkov laboratory

Faculty Research Themes

Infection and Immunology

School Research Themes

Infection & Immunity

Key Contact

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

Department / Centre

Biochemistry and Pharmacology

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