Crossing the periplasmic void, elucidating the mechanisms of phospholipid transport in Gram-negative bacteria

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The ever-increasing resistance of microorganisms to antimicrobial therapies, in particular for Gram-negative bacteria, represents one of the greatest threats to global public health of the 21st century. In fact, in Europe alone, an avoidable 25,000 deaths and 2.5 million days in hospital are thought to be directly related to this rise in resistance, totalling a cost of £1.2 Billion. England's Chief Medical Officer, Professor Dame Sally Davies recently termed antimicrobial resistance "a catastrophic threat", and suggested that without the development of new antibiotics minor operations may become deadly. However, a recent report by the WHO highlighted the alarming lack of new antibiotics under development and found most new drugs in the pipeline to be modifications of existing classes of antibiotics. The development of new antimicrobial agents requires an in depth understanding of how Gram-negative bacteria function and maintain homeostasis. Selecting which of the systems in the bacteria to target signifies a central concept of the drug development programme. One such attractive target is the bacterial cell envelope, with the mechanisms involved in its production and maintenance perhaps holding the key to generating novel antimicrobials. All Gram-negative bacteria possess two membranes (made of lipids) that enclose the cell, separated by a space known as the periplasm. The outer of the two membranes protects the bacterium from the environment and represents its first line of defence by forming a semi-permeable layer through which it controls the movement of molecules into and out of the cell. Furthermore, proteins within this membrane are essential for bacterial pathogenesis and drug resistance. As such they are viewed as the instruments of microbial warfare, mediating the processes responsible for infection and disease progression. Preventing the formation of this membrane through the identification of new compounds could lead to the development of the next generation of antimicrobials.Recently a network of proteins found at both the outer and inner membranes, known as the Mla pathway, was identified as being responsible for the transport of lipids between the two membranes. Recent evidence suggests that the Mla system is important for maintaining both the structure and the function of the outer membrane and can replenish its lipid content by transferring it from the inner membrane. Consequently, the system has been identified as a key modulator of membrane function. It is therefore of critical importance to understand how this system works, as the design of new compounds that inhibit the activity of the Mla pathway could potentially disrupt outer membrane structure and thus inhibit many essential physiological, pathogenic and drug resistance functions of Gram-negative bacteria.In this research project we plan to characterise the mechanistic processes the Mla pathway undertakes in order to transport lipids between the inner and outer membranes, we will identify how the different types of lipids are transferred and the details behind how they are removed from the inner membrane, thus providing valuable mechanistic insights that will aid in the discovery of molecular inhibitors and new classes of antimicrobial agents.