Understanding protein folding and assembly at the outer membrane of pathogenic gram-negative bacteria

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Hazel, Anthony
Gumbart, James C.
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Antimicrobial resistance in pathogenic Gram-negative bacteria is quickly becoming a global pandemic, responsible for approximately two million illnesses and almost 23,000 deaths annually in the United States alone according to a recent report from the CDC. In this presentation, I will use molecular dynamics (MD) simulations to study two new targets in the fight to slow down and, ultimately, halt the spread of resistance. The first target is an autotransporter protein, pertactin, which acts as a virulence factor for infection in Bordatella pertussis. The environment of the cellular envelope creates a unique vectorial folding pathway for the long β-helical passenger domain of pertactin that plays an important role in secretion of the virulence factor. I demonstrate that this vectorial pathway not only stabilizes the β-helix, but creates a downhill folding process that vastly increases the rate of folding and, therefore, secretion. By targeting initial folding intermediates of pertactin, novel drugs could be designed that might severely limit the rate of B. pertussis infections. The second target is the multidrug efflux pump, AcrAB-TolC, in Escherichia coli which can eject antimicrobial drugs and other harmful macromolecules from the cell and is one of the primary mechanisms in E. coli for antimicrobial resistance. Targeting this and other pump complexes with so-called efflux pump inhibitors (EPIs) has the potential to revive the efficacy of antibiotics for which bacteria have already gained resistance. MD simulations and bacterial expression assays show that the conformations of the flexible membrane fusion protein, AcrA, can effect the activity of the entire pump complex. Some previously discovered EPIs that target AcrA may function by limiting or altering the fusion protein's accessible conformations, thus preventing pump assembly.
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