Microbial Genomic Determinants of Antibiotic Treatment Failure in Staphylococcus aureus Bacteremia

ABSTRACT Staphylococcus aureus bacteremia (SAB) is a common and frequently lethal infection. Despite appropriate antibiotic therapy, many patients will experience treatment failure in the form of relapsed SAB (>1 episode with the same isolate) and persistent SAB (>5 days of persistently positive blood cultures). Antibiotic treatment failure is driven by the interplay of host, treatment and microbial factors. Despite decades of research focusing on treatment and patient factors, mortality from SAB remains at 25% and we still know very little about the role of microbial biology in treatment failure. Innovative approaches are required to address this important knowledge gap. To address this problem, Dr. Parsons’ long-term goal is to use patient clinical data, bacterial clinical isolates and focused genomic and laboratory studies to determine the link between bacterial biology on the bench and clinical outcomes in patients. The short-term goal of this proposal is to identify genomic polymorphisms influencing antibiotic treatment failure in SAB patients. The central hypothesis posits that specific genomic changes lead to an enhanced ability to evade the innate immune system and antibiotics, which drives worse clinical outcomes in patients. This will be tested through two specific aims. Aim 1 will identify bacterial genotypes associated with SAB antibiotic treatment failure using murine in-vivo evolution model. Dr. Parsons has developed several S. aureus strains with enhanced virulence and increased antibiotic tolerance via serial passaging through a murine bloodstream. Dr. Parsons will identify genomic changes within these isolates and examine the clinical relevance by screening for these mutations in a prospectively enrolled cohort of patients with relapsed SAB. Aim 2 will identify new bacterial genotypes associated with SAB antibiotic treatment failure. This aim will use a unique high-throughput sequencing and a bacterial Genome Wide Association Study (GWAS) pipeline combined with the world’s largest SAB biorepository to identify genomic variants associated with persistent SAB and relapsed SAB. The work will also focus on unraveling the biological mechanism driving persistent bacteremia of two polymorphisms previously identified using this GWAS technology; plsX and metN2. Identification of genes associated with antibiotic treatment failure in humans will increase our understanding of the devastating outcomes associated with SAB and identify new drug candidates aimed at reducing S. aureus virulence and sensitizing the bacteria to antibiotics. Dr. Parsons’ training to date has focused on the biochemistry of S. aureus metabolism. He will supplement this experience with training in genomics and observational clinical studies to focus on the link between bacterial genomic variations and clinical outcomes. The skills and mentoring acquired during this award will facilitate Dr. Parsons’ development into an independent physician-scientist focused on bacterial determinants of clinical outcomes in bacterial bloodstream infections.