Dr. David Sherratt
University of Oxford

Mechanisms and functions of recombination in relation to dissemination, establishment, and persistence of antibiotic resistance genes.

Many of the diseases relevant to “health disparities” include as a risk factor the possibility of secondary bacterial infections. The current epidemic of superbugs (bacteria resistant to multiple antibiotics) increases the cost of treatment and the mortality rates. Furthermore, another issue relevant to “health disparities” as it infant mortality is greatly affected by the rise in the number of multiresistant pathogenic bacteria.

Our research search concerns the molecular mechanisms of various types of recombination processes, and how these mechanisms relate to biological functions. In this project, those functions are related to bacterial resistance to antibiotics. It is known that an important strategy bacteria utilize to resist antibiotics is through acquiring “resistance genes” usually by plasmid transfer. Plasmids posses a number of mechanisms to ensure their stable maintenance within the host bacterial cells. One of these mechanisms consists of resolution of plasmid dimers, which are formed through recombination events in the cell. Dimerization of plasmids leads to multimer formation, a known cause of plasmid instability. Xer is a site-specific recombination system that catalyzes conversion of plasmid dimers into monomers, ensuring plasmid stability.

The broad objective of this project is the understanding of the molecular mechanisms and interactions of the Xer recombination proteins and the plasmid under the various conditions the host bacterial pathogen may encounter through its life cycle. Upon entering a host, the pathogens' surroundings change dramatically, and they must have systems that enable them to grow or survive. Plasmids harbored by these bacterial cells carry genetic elements to be stably maintained in the various environments, and the molecular mechanisms may have to adapt to these changes. For example, a number of bacterial species cause a substantial amount of hospital-acquired urinary tract infections, pneumonia, septicemias, meningitis, and soft tissue infections. The niches occupied in these diverse infections may present different challenges to plasmids for stable inheritance.