Delivering novel therapeutics to target bio-threat pathogens

DMTC has partnered with the University of Western Australia and Monash University to generate optimised compounds capable of inhibiting multiple bacterial pathogens of interest to Defence.

Potential bio-threat agents include Burkholderia pseudomallei, which causes melioidosis, and Coxiella burnetii which causes Q fever, both of which are endemic in northern Australia and nearby tropical regions. Military personnel deployed to these regions may contract these serious diseases, which can be highly infectious and transmitted by an airborne route. Antibiotic resistance is also increasing in these pathogens, highlighting the urgent need for novel anti-microbial countermeasures with broad spectrum activity.

Macrophage infectivity potentiator (Mip) proteins are found in a wide range of bacterial pathogens including B. pseudomallei and C. burnetii and are known to be important to the survival of bacteria within host cells. Mips are responsible for bacterial protein folding and by inhibiting their activity, the ability for the bacteria to survive within the host is severely limited. Targeting these proteins therefore disables the bacteria and provides the opportunity for the host immune system to fight against infection. The presence of Mips in a wide range of bacterial species also indicates that this is a good target for broad-spectrum therapeutic intervention – using a single drug to target multiple pathogens.

This project team has previously shown that a series of small molecules are capable of inhibiting the Mip proteins of various bacterial pathogens, including B. pseudomallei and C. burnetii. The inhibition of Mip resulted in increased clearance of B. pseudomallei in host cells, and a decreased rate of growth in C. burnetii, indicating that Mip is important for some bacterial species to cause disease, while in other bacterial species it is essential for growth.

The team is now designing and synthesising several new compounds to improve metabolic stability, while ensuring potent efficacy is maintained. These characteristics are essential to enable progression of the project through pre-clinical and clinical development, and the team are also establishing a product development plan and target product profile to map out the long-term development pathway.

The successful delivery of this project will progress a lead series of new compounds that target multiple bacterial infections, including those that are resistant to existing antibiotics, and future work aims to deliver a novel antimicrobial capable of protecting both ADF personnel and the public against the increasing threat of antimicrobial resistance.