Chemical biology probes of protein secretion and lateral gene transfer
The majority of proteins destined for secretion are synthesized with N-terminal leader sequences, which during or after translocation across the membrane, requires SPase for removal. Although SPase plays a central role in the fundamental process of protein secretion, identification of the specific extracellular proteins that rely on its activity has remained difficult. For example, proteomic analysis of secreted proteins is complicated by intracellular contaminants due to unavoidable cell lysis.
With the availability of a potent and specific SPase inhibitor, we can now characterize the proteins that require SPase for secretion - by looking for those proteins whose extracellular concentration shows an arylomycin dose dependence. We are in the process of using the arylomycins to characterize protein secretion in a variety of different human pathogens, including S. epidermidis and S. aureus. This work involves an ongoing collaboration with the Center for Physiological Proteomics (TSRI). Because protein secretion is essential for virulence, as well as for viability, in addition to elucidating fundamental aspects of cell physiology these studies also illuminate the potential of an arylomycin class antibiotic to inhibit virulence while they kill bacteria.
