Biogenesis of the Clostridioides difficile membrane: glycolipid and lipoteichoic acid synthesis

Clostridioides difficile is a major cause of hospital infections that urgently requires new, specific antibiotic treatments. My research focused on the unique outer layer of the C. difficile cell, the cell envelope, to discover novel drug targets. An easy way to think of the cell envelope is as the cell s skin. A key feature of the C. difficile cell envelope is a membrane rich in molecules called glycolipids. I identified two proteins, UgtA and UgtB, that build these glycolipids and showed they are important for the bacterium s survival, shape, and membrane stability. One of these glycolipids also anchors a long surface polymer called lipoteichoic acid (LTA). I discovered two additional proteins, LtaA and LtaB, that are required to build this LTA polymer. My work demonstrated that without these LTA-building proteins, the cells cannot grow properly and ultimately burst. My discovery that these four proteins are important in C. difficile makes them potential drug targets. Since the structure of C. difficile LTA is uncommon, an antibiotic which inhibited the enzymes that build it would likely be deleterious to C. difficile while sparing the beneficial intestinal microbiota. Therefore, my work is an important step toward developing better, narrow-spectrum treatments for C. difficile infections.