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Extracellular heme uptake and utilization in Pseudomonas aeruginosa : It’s not just about the iron!

The ability to acquire iron (Fe) is essential to the survival and virulence of bacterial pathogens within the host. In an effort to combat the invading pathogen the innate immune response sequesters iron from the pathogen, a process termed “nutritional immunity”. P. aeruginosa circumvents these efforts by exploiting a variety of mechanisms to acquire Fe, including heme acquisition by the heme assimilation (Has) and Pseudomonas heme uptake (Phu) systems. Studies in our laboratory have shown P. aeruginosa evolves to utilize heme as the primary source of iron. Furthermore, we have established the Has and Phu systems play essential but non-redundant roles in heme sensing and transport, respectively. Biochemical and biophysical characterization of the heme sensing and transport pathways will be presented. Based on the mechanistic characterization of heme sensing and uptake we have synthesized novel lead compounds targeting these mechanisms. The dual function inhibitors lead to global disruption of iron-homeostasis and virulence, while placing less selective pressure on the bacteria to undergo mutation leading to drug resistance.  

Angela Wilks received her BSc degree in Biochemistry from the University of Lancaster, England. She received her PhD in Biochemistry from the University of Leeds, where she worked on the mechanism of heme degradation with Professor Stanley B. Brown. After a post-doctoral appointment with Professor Paul Ortiz de Montellano at the University of California, San Francisco, she joined the faculty at the University of Maryland as an Assistant Professor in 1998 and has risen through the ranks to Full Professor. She was appointed as the Isaac E. Emerson Professor in Pharmaceutical Sciences in 2017.

Her research interests focus around mechanisms by which bacterial pathogens acquire and utilize heme as an iron source, and their relationship to pathogenesis and virulence. Professor Wilks' research is multi-disciplinary employing bacterial genetics, metabolomics, biochemical and biophysical approaches to understand the molecular mechanisms by which pathogenic bacteria acquire heme. These studies have led to the structural characterization of several proteins involved in heme utilization and to the rational design of novel antimicrobial agents. Professor Wilks is recognized as a leader in the field of metallobiochemistry and has published over ~100 peer reviewed research articles, given over 90 invited lectures and seminars and has been funded continuously by NIH to support her research.

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