Cell wall synthetic lipid microdomains: composition and mechanism of formation

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The wide use of antibiotics in healthcare and agriculture has caused the appearance of bacterial strains that are resistant against most or even all antibiotics. As a result, bacterial infections have re-emerged as a serious health concern, and an increasing financial burden for the healthcare systems. To counteract this trend, research and development of new antibiotics is a top priority. We now need to identify new classes of antibiotics that are not readily compromised by existing resistance mechanisms, and to direct our long-term efforts towards antibiotics with an intrinsically lower risk of resistance development. Historically, our most successful classes of antibiotics have been natural compounds produced by other organisms to counteract bacteria in their environment. These antibiotic classes were identified based on good antibacterial activity, and usually feature a complex antibacterial mode of action with several cellular systems inhibited at the same time. In recent decades, efforts to develop new antibiotics have been dominated by a target-driven approach, which first identifies a single, theoretically good antibiotic target, and then screens for specific inhibitors against it. This approach has largely failed due to the rapid rate of resistance development against single mode-of-action antibiotics. Consequently, we now need to re-focus on antibiotics that do not act by a single inhibitory mechanism. Compounds that target bacterial cell membranes are widely used in nature as antimicrobials. These molecules are produced by other bacteria, fungi, plants and animals to combat undesired bacteria. This evolutionally highly successful strategy has two crucial advantages over our current antibiotics. Firstly, instead of inhibiting gene-encoded targets such as proteins or ribosomes, the cellular targets are membrane lipids. Consequently, mutations that modify the target and thereby prevent the binding do not easily emerge. Secondly, the disruption of the cell membrane simultaneously inhibits a large number of membrane-associated cellular processes, thus making it difficult for bacteria to evolve a meaningful defense. One crucial cellular process disrupted by membrane-targeting antibiotics is the synthesis of cell wall, a rigid structure that encloses the cell and provides it with physical stability. The interference with the cell wall synthesis provides membrane-targeting antibiotics the ability to cause irreversible disintegration of the cell, a process termed bacteriolysis. Consequently, membrane-targeting antimicrobials kill bacteria very rapidly, and the rate of resistance development is either remarkably low or even undetectable. The reason why the bacterial cell wall synthesis machinery is sensitive to membrane-targeting antibiotics has remained elusive. Recently, we showed that proteins responsible for the cell wall synthesis induce a specific area in their membrane surrounding (lipid domain) that differs from the remaining membrane in its properties and composition. Such lipid domains are preferred targets for membrane-targeting antibiotics, hence providing the first plausible explanation why cell wall synthesis is efficiently inhibited. In this project, we will identify the mechanism through which the lipid domains associated with the cell wall synthesis machinery are induced, and characterise their detailed composition. This is important in order to understand how bacteria synthesise their protecting cell wall envelope, and how membrane-targeting antimicrobials kill bacteria by disrupting its synthesis. By providing direct insight into the mechanisms underpinning their potency, our research will guide the design and development of novel membrane-targeting antibiotics that exploit this cellular weak point.