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Research in the Richardson laboratory is primarily focused on understanding the role of bacterial physiology in the pathogenesis of gram-positive bacteria, including Staphylococcus aureus. S. aureus is frequently isolated as the source cutaneous infections as well as more invasive soft tissue infections, surgical site infections, bacteremia, endocarditis, osteomyelitis, pyelonephritis, meningitis, septic arthritis, and necrotizing pneumonia. Over half of nosocomial S. aureus infections are caused by strains resistant to the preferred anti-staphylococcal antibiotic methicillin. The frequency of methicillin resistant S. aureus (MRSA) has risen by 29% in the past four years and has become one of the top ten leading causes of death in the US with an estimated annual cost of $17-$30 billion. Thus, there is a desperate need to develop new antimicrobials to combat S. aureus infections.
The success of S. aureus as a human pathogen hinges in this organism’s ability to withstand the effects of the host innate immune system. A key component of innate immunity is the production of large (millimolar) amounts of nitric oxide (NO•) by activated phagocytes. S. aureus has proven to be significantly more resistant to NO• than many other species of bacteria. This suggests that S. aureus has evolved a means by which it can ameliorate the cytostatic effects of NO• during infection. A major focus of the Richardson laboratory is to uncover how S. aureus achieves NO• resistance and to exploit this trait for the development of new antimicrobial therapeutics.
NO• is a small, uncharged, lipophilic radical with mild oxidizing potential that diffuses from a point of origin (i.e. activated phagocytes), through membranes to form millimeter concentration gradients. Bacteria exposed to host NO• must respond to a wide variety of biochemical insults. In aerobic environments, NO• can chemically modify protein thiols, iron-sulfur clusters, heme cofactors, and tyrosine residues, as well as DNA bases and lipid bilayers. The unique reactivity of NO• towards various redox-active catalytic motifs makes cellular metabolism a prime target. Indeed, the ability of S. aureus to replicate under nitrosative stress relies on the induction of an NO•-resistant metabolic state. Upon NO•-exposure, S. aureus evokes a homolactic fermentative physiology stemming from the induction of a S. aureus specific lactate dehydrogenase, ldh1. This allows S. aureus to maintain redox balance, even in the face of NO•-mediated inhibition of cellular respiration. Additionally, activation of the S. aureus flavohemoprotein encoded by hmp is also necessary for NO•-resistance. This enzyme detoxifies NO• via a denitrosylase reaction generating the less reactive nitrogen-oxide, nitirate (NO3-).
The hmp-ldh1 locus represents two facets of S. aureus NO•-resistance: enzymatic detoxification and metabolic adaptation. The mechanism by which S. aureus senses and responds to host NO• is still unknown, but the hmp-ldh1 locus provides an excellent system to uncover the regulatory mechanisms behind S. aureus NO•-resistance. Furthermore, S. aureus provides a relevant model to begin addressing the important role of bacterial physiology in the virulence of pathogenic microorganisms.
In a broad sense, the Richardson laboratory combines bacterial genetics, molecular biology, microbial physiology, and bioinformatics to study the role of bacterial metabolism in the pathogenesis of infectious diseases.