New and Noteworthy Research Receives a 2 Year R21 Grant

 

The Brinsmade lab has just received an NIH Exploratory/Developmental Research Grant to foster their research and to help encourage further investigations. With a specific interest in cellular metabolism, gene expression, and microbes, Professor Brinsmade and his group are working to understand the interface of metabolism and pathogenesis in Gram-positive bacteria using Staphylococcus aureus as a model pathogen. Previous work from the Brinsmade lab has shown that the S. aureus global regulatory protein CodY helps to suppress the production of virulence factors when activated by the amino acids isoleucine, leucine and valine (ILV), and guanosine triphosphate (GTP). In the absence of active CodY and suppression, toxins and other disease-causing factors are elevated and those bacteria are significantly more virulent. Moreover, maintaining activity during growth keeps CodY-dependent genes repressed. Therefore, CodY could be exploited as an anti-virulence therapy and allow at-risk patients to clear the infection naturally. Before doing so, it is essential to establish that CodY activity changes in the bacteria associated with host tissues during infection. If so, administering analogs of ILV and guanine nucleotides that prevent loss of CodY activity could potentially prevent staphylococcal disease. The grant seeks to do two things to reveal the relationship between CodY, host nutrients, and regulation of gene expression: i.) assess whether host tissue affects CodY-dependent gene expression using cutting edge in vivo and ex vivo live imaging and fluorescent reporters, and ii.) determine whether increasing ILV abundance in staphylococci during infection affects pathogenicity. Brinsmade and his lab members collaborate with staphylococcal biologist Michael Otto (National Institutes of Health), and preclinical imaging experts led by Christopher Albanese (Georgetown University Medical Center). Together, they will employ a multifaceted approach to gain a deeper understanding of CodY function in vivo and to test this anti-virulence approach. For more information on the Brinsmade lab, check out the lab website at https://brinsmadelab.com/. You can also follow Prof. Brinsmade (@SBrinsmade) on Twitter!

“Community-Acquired Staphylococcus aureus strains are often resistant to current drugs, are particularly aggressive, and threaten the lives of healthy individuals by producing toxins and tissue- damaging factors at the precise time and location in the host during infection. Because a loss of CodY activity dictated by the concentration of certain amino acids and energy molecules in laboratory cultures leads to a programmed control of the genes encoding disease-causing factors, maintaining active CodY by increasing the concentration of these key nutrients is a potential strategy for shutting off the ability of these bacteria to sicken their hosts.”