Identifying Inhibitors of ZipA Through Computational and Biochemical Screening

Many formerly treatable bacterial infections are becoming harder to cure because widespread overuse of antibiotics has led to the development of antibiotic resistant strains. The aim of my project is to find a new antibiotic that will disable bacteria by a different mechanism than current antibiotics. A new possible pathway to inhibit bacterial growth is by interrupting the interaction of two proteins involved in cell division, ZipA and FtsZ. The interaction between ZipA and FtsZ is found in the vast majority of bacteria so interfering with it with a small molecule should be effective for many different bacterial strains. The mechanism is that first, multiple FtsZ proteins creates a loop of  incomplete cytoskeletal filaments which are called the Z-ring. The Z-ring spans the equator of the cell just underneath the cytoplasmic membrane. During cell division, ZipA binds to FtsZ which causes the filaments to connect and a solid loop to form across the middle of the bacterial cell. This loop then shrinks at the end of cell division, causing the telekinesis of the cell into two distinct cells, thus reproducing more bacteria. Without ZipA, the fragments do not connect or condense to divide the bacteria. An effective antibiotic would inhibit the interaction in between ZipA and FtsZ. A small molecule would be put in the binding site on FtsZ, hindering the ability of the ZipA to bind. The small molecule would outcompete the ZipA and effectively stop cell division in the bacteria.