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Targeting Type IV secretion traffic ATPases to stop dissemination of antibiotic resistance genes

AuthorsGarcía-Cazorla, Yolanda; Cruz, Fernando de la ; Arechaga, Ignacio ; Cabezón, Elena
Issue Date2017
Citation42nd FEBS Congress (2017)
AbstractAntibiotic resistance is becoming a pressing public health concern. The main mechanism for the dissemination of antibiotic resistance genes between gram-negative bacteria is the horizontal transfer of genetic material in a process known as conjugation. Therefore, the search for specific conjugation inhibitors (COINs) is crucial for winning the battle against antibiotic resistance bugs. Unsaturated fatty acids (uFAs) and 2-alkynoic fatty acids (2-aFAs) are the only effective and specific inhibitors of conjugation found so far. We have found that the Type IV secretion system ATPase TrwD, the VirB11 homolog in the conjugative plasmid R388, is the molecular target of these inhibitors. VirB11 proteins belong to the super-family of secretion AAA+ traffic ATPases. These proteins form hexameric rings in which each monomer is caracterized by a catalytic region (C-terminal domain, CTD) and a region that interacts with the cytoplasmic site of the membrane (N-terminal domain, NTD) connected both of them by a flexible linker of a variable length. We have identified the mode of action: COINs bind to a pocket comprised by NTD and linker, preventing the pivoting movement of NTD over CTD. Interestingly, even though saturated fatty acids are not COINs, palmitic acid (major component of bacterial membrane phospholipids) interacts directly with TrwD and binds to it. Characterization of kinetic parameters and docking predictions indicate that uFAs and saturate palmitic acid compete for the same binding site of TrwD. Moreover, uFAs incorporate to the bacterial membrane when added to the growth media, affecting the natural phospholipid composition. All this suggests that the mode of action is by affecting the interaction of TrwD with the bacterial membrane. In short, our results do not only contribute to a better understanding of VirB11 proteins but also lie the foundations for the rational design of more potent and effective drugs to control dissemination of antibiotic resistance genes.
DescriptionResumen del póster presentado al 42nd Federation of European Biochemical Societies (FEBS) Congress: "From Molecules to cells and Back", celebrado en Jerusalem (Israel) del 10 al 14 de septiembre de 2017.
Appears in Collections:(IBBTEC) Comunicaciones congresos
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