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High-through Phenotyping Of Staphylococcus Aureus Isolates From Diabetic Foot Ulcers Reveals Virulence Behaviors Associated With Clinical Outcomes
Amelia R. McCready-Vangi1, Amy E. Campbell1, Sue E. Gardner2, Elizabeth A. Grice1.
1University of Pennsylvania, Philadelphia, PA, USA, 2University of Iowa, Iowa City, IA, USA.

BACKGROUND: Diabetic foot ulcers (DFU) are a common complication of diabetes. Up to 25% of diabetic patients will develop a DFU in their lifetime. Understanding the factors that contribute to healing and complication is essential to address the urgent need for both novel therapeutics and diagnostic tools for patients with DFU. One such factor is the colonizing microbiota, which in DFU is commonly dominated by the skin and soft tissue pathogen, Staphylococcus aureus.
METHODS: Previous metagenomic analysis of a prospective cohort of neuropathic, uninfected DFU (n=46) demonstrated that although most wounds are colonized with S. aureus to some degree, strain-level variation of this pathogen was associated with clinical outcome. We therefore hypothesized that S. aureus strains isolated from these DFUs would display differential virulence behaviors that correlate with clinical outcomes. To address this hypothesis, we screened a library of 224 S. aureus isolates cultured from a longitudinal, prospective cohort of n=100 DFU patients. High-throughput, quantitative phenotyping assays were optimized to examine the behavior of each of these strains in vitro, including: 1) biofilm formation; 2) production of the pigmented virulence factor staphyloxanthin; 3) siderophore production; and 4) phenol-soluble modulin-mediated colony spreading.
RESULTS: We found that S. aureus strains producing high staphyloxanthin are significantly associated with a non-healing wound phenotype (T-test p-value= .032) and that in vitro biofilm production was not correlated with healing phenotype (T-test p-value=.544).
CONCLUSIONS: In our ongoing work, whole genomic sequencing of these 224 isolates to enable genetic association analysis will identify genetic loci and putative genes associated with in vitro virulence phenotypes and clinical outcomes. We will validate these results using transposon mutants and in vivo studies. Our work has the potential to inform DFU patient care by providing insight into what constitutes problematic bioburden and S. aureus colonization, thus providing novel diagnostic and therapeutic targets.


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