Developing novel antibiotics from natural products against resistant bacteria

Identified by the World Health Organisation (WHO) as one of the top 10 threats to global health, antimicrobial resistance threatens our ability to treat infections and leads to the rise of multi-drug resistant bacteria. As drug-resistance spreads globally, the antibiotics in current use are becoming increasingly ineffective and the clinical pipeline for new drugs is lacking, with only six new antimicrobials being classed as innovative against the WHO's list of priority pathogens. Antimicrobial resistance occurs when pathogens such as bacteria mutate, resulting in gained mechanisms that lead to resistance against drug treatments, making bacterial infections easier to spread and difficult to treat. Carbapenems are reserved as a 'last resort' against multi-drug resistant bacteria, however carbapenem-resistant bacteria have now been identified and are deemed to be a critical priority by the WHO. Resistance to carbapenems is a result of B-lactamase enzyme activity within bacteria and can be split into two categories, either using a serine residue or a metal ion, i.e., Zn2+, that activates nucleophilic water molecules to hydrolyse the B-lactam ring of a drug present in the B-lactamases active site. Whereas serine B-lactamase inhibitors are widely available as part of a combination with existing B-lactam antibiotics to overcome resistance, there are currently no available drugs that are able to target metallo B-lactamase enzymes (MBL) clinically. Through targeted screening, it was found that a natural fungal product Aspergillomarasmine A (AMA), could inhibit MBLs and also synergistically restores the activity of drugs against resistant isolates.
Based on AMA structure activity relationships, further structural modifications on the AMA scaffold can be made using medicinal chemistry approaches. These modifications can be used to improve potency, selectivity and other drug-like properties of AMA. As a result, the research to be conducted within this project is aimed at designing, synthesising and biologically evaluating novel antibacterial agents using an AMA-based scaffold to target metallo B-lactamases. The findings of this project will help to address important global health issues arising from the significant increase in antimicrobial-resistant bacteria. The study will focus on new MBL enzyme inhibitors, giving rise to new potential treatments or laying the foundations for future work on this class of drugs. As a result, by completing this research we will advance the scientific knowledge against antimicrobial-resistant bacteria and provide possible alternatives for treatment against drug-resistant bacteria.