A Career Developing Biotech Methods to Treat Bone Infections

April 21, 2021

Biotechnology approaches, including genome engineering, are being used to combat pathogenic microbes.
Lauren Priddy.
Lauren Priddy.
Dr. Lauren Priddy, Assistant Professor of Biomedical Engineering at Mississippi State University, and her team recently developed a novel CRISPR-Cas9 modified bacteriophage to treat antibiotic resistant bacterial strains, such as Staphylococcus aureus. This novel microbe control strategy helps to specifically target the pathogen with greater efficacy. In this interview, she discusses her research in controlling bone infections and using advanced biotechnology approaches for biomedical applications. She took her passion for mentoring young women scientists to co-found BioIgnite, an Atlanta-based nonprofit that promotes biomedical science, technology, engineering and mathematics (bioSTEM) education for middle school students.

What inspired you to focus on bone infections? 

When my grandfather was young, he had a staph infection of his femur that required surgery and aggressive antibiotic treatment. Fortunately, he recovered fully because of his treatment with the recently discovered antibiotic, penicillin. If left untreated, his infection could have cost him his leg or even his life. 

Osteomyelitis, or the infection of bone, is most commonly caused by Staphylococcus aureus strains and can lead to prolonged hospital visits and in more extreme cases, amputation of affected limbs. Although the prevalence of bone infections is relatively low compared to rates of other infected tissues, once bacteria colonize the bone and/or orthopedic implant, and enter a biofilm state, clearing the infection becomes even more challenging. Difficulties in treating osteomyelitis have been exacerbated by the rise of antimicrobial resistant (AMR) bacterial strains, and chronic infection remains a huge clinical burden. This clinical challenge motivates my lab’s work, which is to develop new therapeutic strategies for mitigating infection and improving bone healing.

What are the challenges of controlling bone infections with the currently available therapeutic molecules in the market? 

Osteomyelitis is an often-chronic infection of bone and/or bone marrow, which may originate from a wound or fracture or may spread to the bone from the bloodstream. The vulnerability of host bone tissue and orthopedic hardware to biofilm-forming strains of Staphylococcus aureus results in significant loss of bone tissue by necrosis/destruction and the necessary removal of this tissue. For decades, the most common therapeutic agents for osteomyelitis have been antibiotics. Typical treatment involves removal of tissue followed by aggressive, prolonged antibiotic administration, which can result in adverse effects, including kidney and liver toxicity, and lead to bacterial resistance to antibiotics. Despite incremental progress towards combating infections, chronic infections remain a huge clinical burden, largely due to increased resistance to antibiotics, high rates of relapse and significant loss of tissue volume from necrosis and tissue removal. Our lab is evaluating fosfomycin, a unique, broad-spectrum antibiotic that has shown effective penetration of bone tissue at only one-tenth the dose compared to the more commonly used antibiotic, vancomycin. Fosfomycin is attractive because it irreversibly interferes with the first step of peptidoglycan synthesis (a component of bacterial cell walls) by inhibiting phosphoenolpyruvate synthetase, leading to bacterial cell lysis and death.

How did you come up with a CRISPR-Cas9 modified bacteriophage technology for controlling Staphylococcus aureus infections? 

By studying bacteriophage therapy for osteomyelitis, we hope that it will serve as an alternative or complement to antibiotics, reducing the risk of emergent AMR bacteria. Traditionally, bacteriophage have great efficacy in lysing bacteria, with high specificity and good biocompatibility for targeting only bacteria. However, phage are often limited in their range of bacterial specificity. Our collaborators, Drs. Keun Seok Seo and JooYoun Park used CRISPR-Cas9 genome editing techniques to enable a temperate bacteriophage with a wider range of specificity. Based on the success of the phage against dermal infections, we hypothesized that the CRISPR-Cas9 modified phage would also reduce S. aureus bacterial burden in soft tissue and bone. We evaluated the efficacy of fosfomycin, phage and dual fosfomycin+phage therapeutics, delivered locally via injectable alginate hydrogel, against a biofilm-forming strain of S. aureus in our chronic, implant-based rat model of composite femoral and soft tissue infection. While all 3 treatment groups reduced bacterial burden in soft tissue, only the fosfomycin group lowered bacterial counts in bone, likely resulting from the relatively low dose of phage compared to the high dose of fosfomycin utilized.  

What are the advantages of using therapeutic materials over therapeutic molecules for treating bone infections? 

Therapeutic materials can be designed for targeted, prolonged drug delivery which has many benefits:
  • Lowering the dose of antibiotics needed. 
  • Abrogating the need for long-term, systemic antibiotics. 
  • Minimizing the risk of toxicity and bacterial resistance. 
The overall goal of my infection research program is to increase efficacy against S. aureus osteomyelitis by designing delivery vehicles that are better equipped at localizing therapeutics for prolonged bioavailability at the site of infection. Recently, we have begun leveraging chitosan-based biomaterials, which possess inherent antimicrobial and temperature-responsive properties, for enhanced spatiotemporal control of therapeutics.

What are your strategies for mentoring students in your lab? 

Mentoring students in research starts with transparency, equity and integrity in how I conduct myself and make decisions for the lab. I aim to be transparent in my decision making by communicating effectively and often. I believe my team is more likely to respect my decision if they understand my reasoning (even if they don’t agree). Each student has a unique background, perspective, skillset and set of goals. I strive to meet students where they are, tailoring my mentoring to what best helps them achieve their goals. I facilitate students’ projects without micromanaging and provide students the freedom to direct their work, as I believe this promotes their learning and growth. I create a collaborative learning environment that simulates settings that students will be exposed to in their future careers and provides them opportunities to hone their leadership and communication skills. In summer 2020, I began incorporating a “minute for diversity, equity and inclusion” into our weekly lab meeting, a dialogue that I hope is helping us learn together and forge a path for a better tomorrow.

What are the key leadership qualities that young scientists should develop? 

The ability to communicate your work effectively, especially to those outside of your field, by telling a compelling, coherent story that people are interested to hear, is critical to success in science and engineering. Especially as biomedical engineering becomes more cross-disciplinary, our successes as researchers are dependent on our ability to work alongside and learn from others.

What advice do you have for young women entering the field of science? 

My advice for young women is to find what you enjoy and confidently give it your all. Find mentors who lift you up and who give you honest, constructive feedback. That being said, you are your best compass. Filter all advice (however well-meaning) through your own lens, prioritizing what is most important to you and your definition of success. 
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Author: Navanietha Rathinam

Navanietha Rathinam
Navanietha Rathinam is a Research Scientist in the Department of Chemical and Biological Engineering at South Dakota School of Mines and Technology.