Mechanism of pilus biogenesis by bacterial conjugative transfer systems

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The rise of antibiotic resistance is one of the major threats to public health. Antibiotics have been the standard of care for bacterial infections for decades. Since their discovery, hundreds of millions of humans have successfully been treated by these "wonder" drugs. Unfortunately, the rapid spread of antibiotic resistance genes among bacterial pathogens threatens to undo the remarkable progress made over the years to combat bacterial infections. Conjugation (or conjugative transfer) is a widespread biological process whereby genes are exchanged horizontally and unidirectionally from a bacterial donor cell to a bacterial recipient cell. Because conjugation is the process via which antibiotic resistance genes propagate among bacterial pathogens, it is in large part responsible for the antibiotic resistance crisis that humanity is presently experiencing. Crucial to conjugative transfer is the prior formation of a pilus, a long hollow filament produced by the donor cell. The pilus is made of 1000s of subunits of a protein called VirB2. The pilus serves not only to make contact with the recipient cell but also as a conduit for the transfer of DNAs from donor to recipient cells. A pilus needs to be generated before DNA transfer can begin. Pilus biogenesis and DNA transfer are mediated by a very large molecular machine called "conjugative transfer system" which is embedded in the membranes of the donor cell. Although 12 proteins, named VirB1-11 and VirD4, are necessary to carry out pilus biogenesis and DNA transfer, only the VirB2-11 proteins are required for pilus biogenesis. Recently, we have determined the cryo-EM atomic resolution structure of a large complex containing all the 10 proteins involved in pilus biogenesis and, as a result, we were able to propose a plausible mechanism for pilus biogenesis. Here we propose to build on this recent work and elucidate the details of the mechanism of pilus biogenesis by these complex systems. Mechanistic and structural details will lead to a better understanding of how antibiotics resistance genes spread among bacterial populations and therefore will provide the means to block it.