Role of branched-chain fatty acids in physiology and virulence of Staphylococcus aureus

7. Project Summary/Abstract
Bacterial pathogens encounter a multitude of chemical and biological insults during infection, including attack by
host immune cells. These stimuli shape the evolution of the pathogen and prompt the development of response
systems to swiftly counter these hostile environments. Two-component systems (TCSs) are the predominant
sensory system for perceiving these stimuli and mediating transcriptional responses to adjust metabolism and
virulence factor production to evade or subvert the host response. Not surprisingly, there is a great deal of interest
in understanding mechanistically how these TCSs function, and how they regulate their gene targets. The PI’s
laboratory studies intersections of metabolism and pathogenesis, with an interest in gene regulation. Several
years ago, the PI’s laboratory discovered that the global regulatory protein CodY regulates the production of
many of the virulence factors of Staphylococcus aureus indirectly through what is arguably one of the most
important virulence regulators in S. aureus – the SaeRS TCS. The SaeRS system has emerged as one of the
most heavily studied TCSs in S. aureus, mainly due to the non-canonical architecture of its membrane sensor
kinase. In recent years, the PI’s group has reported that the effect of CodY on SaeRS function is multifaceted.
CodY acts as a transcriptional repressor to prevent SaeRS activity from becoming unlimited. It also acts post-
transcriptionally to upregulate SaeRS activity. Both functions occur when key amino acids are limiting, reducing
CodY’s regulatory activity. The PI’s laboratory studies the nutritional regulation of pathogenesis in S. aureus.
The long-term goal of the work supported by R01-AI137403 is to understand how metabolism fuels infection,
and how metabolism and virulence are intertwined. The PI’s group will continue probe the mechanisms of SaeRS
control using comprehensive genetic, molecular biological, biochemical and system-wide approaches. Herein,
they propose to 1.) gain insights into the mechanism of SaeRS regulation by branched-chain fatty acids, 2.) to
define the pathways used to synthesize these fatty acids that are an essential component of staphylococcal
membranes, and 3.) to gain a better understanding of how branched-chain fatty acids are integrated into the
overall virulence regulatory network of S. aureus during skin and soft tissue infections. In doing so, the PI’s group
will provide the framework for potentially novel anti-virulence strategies.

Grant Number: 2R56AI137403-06A1
NIH Institute/Center: NIH
Principal Investigator: Shaun Brinsmade