1. Biogenesis of surface-exposed lipoproteins (SLPs). Recently discovered SLPs play critical roles in pathogenesis Gram-negative pathogens and are proven vaccine targets. Despite their biomedical importance, the mechanism underlying lipoprotein localization to the cell surface is the least understood aspect of bacterial envelope biogenesis. Our goal is to define the mechanism of lipoprotein targeting and export to the bacterial cell surface. Improving our understanding of molecular determinants for export will enable the development of predictive computational models for lipoprotein localization and genomic identification of SLPs. The knowledge gained from the proposed studies will aid in the identification of novel vaccine targets, necessitated by the rise of antibiotic resistance in Gram-negative pathogens.

2. Envelope stress responses. Because the OM integrity and barrier function is essential for survival, the OM itself, as well as its biogenesis pathways, have emerged as a major target of the antibiotic development. Very few small molecules inhibitors of these pathways have been identified due, in part, to the extraordinary functional robustness of the envelope. This robustness is achieved through the bacterial envelope stress responses. These pathways monitor the structural and functional integrity of envelope components; when the integrity is compromised, they mediate the signal transduction inside the cell to regulate gene expression to minimize the damage and promote the survival. We study the envelope stress responses both on the molecular and the system level. We aim to fill up the critical gap in the understanding the global regulatory networks that ensure the fidelity of the envelope assembly under different growth conditions, including antibiotic challenges.