Micobial Pathogenesis and Immunity Group

Lab head: A/Prof James Triccas
Location: Blackburn Building The University of Sydney, Camperdown Campus

The research programme of the laboratory is divided into three main areas:

New vaccines to combat tuberculosis: Our focus in recent years has been to develop and assess live vaccines engineered to augment components of the immune response required for optimal anti-tuberculosis protective immunity. This has included the use of BCG strains engineered to secrete cytokines or chemokines that influence the number and activation state of dendritic cells (DCs) in order to enhance T cell immunity and pathogen elimination. Some of these vaccines have shown promise in our pre-clinical models of tuberculosis infection, and are undergoing further appraisal as candidates to control M. tuberculosis infection in humans. In parallel, attenuated strains of M. tuberculosis are being developed and tested for their vaccine potential.

Defining immunity induced by infection with Mycobacterium tuberculosis and new tuberculosis vaccine candidates: By the use of recombinant mycobacterial strains expressing reporter proteins and transgenic T cell systems, we are defining in detail the parameters associated with optimal protective immunity against tuberculosis. We are also using confocal microscopy and live-cell imaging to examine the relationship between mycobacteria and host cells. The information derived from the studies will aid selection of suitable mycobacterial strains for future development as anti-tuberculosis vaccines.


 

Identifying and developing new antibiotics to treat drug-resistant bacteria. 

We are using high throughput screening of natural product libraries and medicinal chemistry approaches to find and develop new antibiotics against pathogenic mycobacteria, drug resistant Pseudomonas and MRSA. We undertake initial compound identification and validation together with analysis of drug safety and efficacy using in vitro and in vivo model of bacterial infection. 

Screening natural products for new anti-bacterial compounds

Primary supervisor: James Triccas

 

Antibiotic-resistant bacteria are emerging at an alarming rate. Certain strains of Mycobacterium tuberculosis, the causative agent of tuberculosis, are resistant to all currently available drugs and these strains pose a major worldwide health problem. Another important bacterial pathogen, Pseudomonas aeruginosa, encodes a multitude of drug-resistance mechanisms and isa major cause of hospital-acquired infection, in particular burns and wounds. In addition, infection with P. aeruginosais the major cause of mortality in people living with the genetic disorder cystic fibrosis (CF), and strains that chronically infect CF patients tend to be highly drug-resistant. 

In this project we will identify new compounds to treat infection with pathogenic mycobacteria and P. aeruginosa. A library of natural products sourced from The Australian Institute of Marine Sciences (AIMS) will be screened to identify novel compounds with anti-bacterial activity. This will involve high-throughput screening of the AIMS library using our established plate-based assays of bacterial growth. The potency of compounds will be examined by determining their minimal inhibitory concentration against P. aeruginosa and mycobacteria grown in culture medium. The inhibitors will also be tested for host cell toxicity to select those with potential for human use. The structures of inhibitors will be examined to determine if unique anti-bacterial compounds have been identified.

As drugs for use in humans should be able to access compartments of the host where the target pathogen resides, the project will also determine if compounds can enter infected cells and kill intracellular bacteria, using both macrophages (for mycobacteria) and epithelial cell lines (forP. aeruginosa). Finally, the ability of novel inhibitors to limit bacterial colonisation and growth in a mouse model of lung infection will be determined. This will permit selection of inhibitors that are able to reduce infection in the whole animal, thus providing lead candidates for development of anti-bacterial compounds for use in humans.

This project will give the student experience in bacterial culture, high-throughput screening of compound libraries, cell culture, animal handling and infection model. 


Discipline: Infectious diseases and Immunology
Keywords: Infectious Diseases, Antibiotics
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