Overview: The discovery and development of antibiotics have saved millions of lives and revolutionized modern medicine. However, the alarming rise in multidrug-resistant (MDR) bacteria has threatened the usefulness of our current arsenal of antibiotics, leading the World Health Organization (WHO) to suggest an impending post-antibiotic era, where minor infections would become lethal. It is anticipated that the global magnitude of this ever-worsening crisis will reach a point where deaths from MDR bacterial infections will exceed even cancer-associated fatalities by the year 2050. This crisis is exacerbated by a chronic shortage of antibiotics capable of treating infections cause by MDR pathogens.
Research Focus: Research in the Pilch lab is focused on the identification of novel antibacterial targets and the development of new antibiotics that can be used in the treatment of infections caused by MDR bacterial pathogens of acute clinical importance. Toward this goal, the lab is working on developing agents that target essential cell division proteins, such as FtsZ. More than 90% of all bacteria require FtsZ to undergo cell division, including many MDR Gram-positive and Gram-negative pathogens. As schematically depicted below, FtsZ forms the scaffold that underlies the cell division machinery (termed the divisome) and recruits key division proteins, including the penicillin binding proteins (PBPs) that drive synthesis of the cell wall.
Role of FtsZ in Septum Formation and Bacterial Cell Division
Among the MDR pathogens being studied in the lab are methicillin-resistant Staphylococcus aureus (MRSA) vancomycin-resistant enterococci (VRE), Klebsiella pneumoniae, Pseudomonas aeruginosa, and Acinetobacter baumannii. One of the lead agents (TXA709) developed in the lab is currently undergoing clinical trials for the treatment of MRSA infections.
Current Projects: Projects in the Pilch lab incorporate a collaborative multi-disciplinary approach that includes structure-guided design, synthesis, mechanism-based in vitro and bacterial studies, as well as in vivo evaluations in mouse models of infection. Current projects include the following:
1. Development and characterization of new FtsZ-targeting agents geared toward combating MRSA and Gram-negative bacterial infections resistant to current standard-of-care drugs.
2. Identifying antibiotics (such as PBP-targeting β-lactam antibiotics) that act synergistically when used in combination with experimental FtsZ inhibitors and defining the mechanism of antibacterial synergy. Explore the impact of such combination drug regimens on the frequency of resistance. To forward this project, we have generated MRSA strains that express a fluorescent FtsZ fusion protein as well as fluorescent PBP fusion proteins. The figure below shows how we have used such constructs to explore the impact of a FtsZ inhibitor (TXA707) on the localization of FtsZ and PBP2a, the protein that makes MRSA intrinsically resistant to β-lactam antibiotics.
DIC and Fluorescence Micrographs Showing the Impact of the FtsZ Inhibitor TXA707 on the Localization of FtsZ (red) and PBP2a (green) in MRSA.
3. Use a novel fluorescence-based technology developed in the lab to study the mechanism of bacterial cell division and the precise role that FtsZ plays in formation of the divisome.
4. In collaboration with the Max Planck Institute for Marine Microbiology in Germany, use the fluorescence-based technology developed in the lab to identify bacterial species in global marine environments and monitor cell division in those bacteria.
