The action “Modular Design of Bacterial Lipid Mimics for Next-Generation Antimicrobials” aimed to drive the discovery of new compounds active against bacteria, to tackle the growing antimicrobial resistance (AMR) crisis. The lack of new antibacterial compounds appearing in the last 20 years is a major cause for concern for all of society. Many older treatments are now defunct and cannot be used for infections due to the resistance that bacteria have evolved against them. As a result, common infections can once again become fatal. Therefore, it is crucial that new treatments are devised which prevent bacteria from becoming resistant, which this project aims to address. Killing bacteria requires some target component of the cell to be disrupted, to either kill the cells or prevent them multiplying. Targets often include specific parts of the cellular machinery, such as enzymes involved in protein or DNA production. However, through evolution bacteria can adapt several strategies, such as changing the structure of the target or pumping the drug out of the cell.
One route to kill bacteria which is more difficult to develop resistance against is to target the cell membrane: the envelope of lipids that protects it from the surrounding environment. However, the major challenge in targeting a membrane is designing a compound which only affects bacterial cell membranes, while leaving membranes from other types of cells unharmed, i.e. the host animal and plant. One way in which bacterial membranes differ from human cell membranes is in the type of lipid molecules that build them, and also the number of layers of lipids. Therefore, finding molecules that bind and break bacterial lipid membranes selectively requires testing many combinations of compounds. To maximise the chances of locating the “golden bullet” molecule against bacteria, I adopted a “high-throughput” approach to screen a large range of compounds. In this, more than 100 different combinations of molecular building blocks are trialled against bacteria, each of which has a subtly different shape. In this way, hit compounds can more quickly be identified. Previously, it has not been well understood how the shape of a molecule affects its antibacterial activity, nor why shape might be an important factor. This project was designed to study a huge library of molecules with different shapes to gain insight into which molecules can disrupt bacterial membranes and destroy their structure, whilst leaving human or other host cells unharmed.
The main objectives of this project centre around the design of new antibacterial “lipidoids”: molecules that resemble the components of cell membranes but which can also disrupt them. Objectives of the action were to i) synthesise a library of lipidoids and characterise their structure and purity, ii) test the antibacterial properties of the compounds against a range of bacterial species and their toxicity to mammalian cells, and iii) garner information on the mechanism of action of the compounds against biological membranes.
