Killing bacteria from within: In search of novel antibiotic targets

The threat posed to human life by infectious diseases cannot be underestimated, as the SARS-CoV-2 viral pandemic highlighted. Of the 56 million global deaths a year, 18% are due to infectious diseases. Mortality is not the only burden; the United Nations estimate the cost of the SARS-CoV-2 pandemic will be US$1 trillion. Secondary bacterial infections significantly impact during viral pandemics, as has been observed with first HIV and now SARS-CoV-2\.

Tuberculosis, caused by the bacterium _Mycobacterium tuberculosis_ (Mtb), is the world's deadliest infectious disease, leading to 10 million cases and 1.6 million deaths per annum. Resistance of pathogens, the causative microorganisms of infectious disease, to drugs is a cause for grave concern. Drug-resistant Tuberculosis is predicted to cost the world $16.7 trillion by 2050\. Discovery of new drugs to treat infectious diseases is both expensive and time consuming, costing US$1 billion and taking 15 years. This process is not fast or agile enough to keep pace with new or resistant infectious diseases. A new approach, concentrating on novel drug targets and approaches, fuelled by more investment, is required to combat the threat of new infectious diseases and drug resistance of pathogens.

The ability of a pathogen to cause disease is directly linked to how well this microorganism can adapt to the host it infects. An example of a highly host-adapted pathogen is Mtb, which has evolved to evade and then reside in the cells of the human immune system, the bodies primary means of combatting infections. In addition, there are bacteria that are related to Mtb that are also human pathogens, which predominantly afflict immunocomprised patients, leading to pulmonary and skin diseases. These Non-tuberculous Mycobacteria (NTM) are difficult to treat due to lack of specific treatments and multidrug resistance.

This project will use a set of chemical compounds, selected due to their similarity to metabolites, small molecule substances that are readily found in bacteria. This compound set will be tested against Mtb and three NTMs to identify those that affect growth. Detailed, cutting-edge studies on live microbes will be carried out to identify how the compounds are interfering with bacterial processes. Finally, the biological targets of the compounds will be identified, and the interactions characterised to determine whether these are suitable for future drug discovery efforts. Sensitivity of the _Mycobacteria_ to the compounds will provide comparative information leading to identification of novel approaches for new drugs.