Sprecher: Antonio Calabrese (University of Leeds)
Antibiotic resistance is projected to cause 10 million deaths per year by 2050, with gram-negative (diderm) pathogens comprising 9 of the 12 bacteria that pose the greatest threat to human health (World Health Organisation). These gram-negative pathogens have a unique outer membrane (OM) that acts as a first line of defence against an assault from potentially harmful molecules to the bacteria, such as antibiotics. As a result, this OM is essential for bacterial survival and is one reason why certain bacteria develop resistance to different types of antibiotics. Finding ways to prevent correct assembly of the OM may therefore produce new routes to kill gram-negative bacteria, or make them more susceptible to existing antibiotics. However, it remains unclear how the OM is built, making its assembly difficult to target with therapeutics. Recently, we have been studying the mechanism by which beta-barrel outer membrane proteins (OMPs) reach the OM. Key to this process are periplasmic chaperones, such as Skp and SurA, which bind to unfolded or partially folded OMPs, preventing their aggregation, and transporting them across the periplasm. The chaperones then deliver their OMP cargos to BAM which folds/inserts OMPs into the OM. Despite the importance of this process, it remains unclear exactly how Skp, SurA and BAM choreograph OMP biogenesis. Using an integrative structural biology approach we are now beginning to illuminate the secrets of the OMP assembly line, which is a key first step in identifying weak points that could be targeted by novel modulators of bacterial virulence and survival.