West Virginia University microbiologists have identified an antibody that can kill one of the most drug-resistant bacteria. Now, they want to determine whether it can be combined with other antibiotics to produce a potent treatment against infection.
The project focuses on the bacterium Pseudomonas aeruginosa, which causes a wide range of diseases including sepsis and pneumonia as well as other acute and chronic infections to the skin, eyes and lungs.
“This pathogen is becoming extremely highly resistant to antibiotics. There are even strains of P. aeruginosa that are resistant to all antibiotics available right now,” said Mariette Barbier, associate professor and chair of the Department of Microbiology, Immunology and Cell Biology in the WVU School of Medicine. “These problems make the treatment of P. aeruginosa infections particularly challenging.”
Infections usually occur in health care settings and spread from contact with contaminated surfaces or medical equipment and from person to person. People who are immunocompromised and those who had a recent surgery are most susceptible. People with the genetic disease cystic fibrosis also experience reoccurring P. aeruginosa infections.
While working to develop a vaccine to prevent the infection, Barbier and her team took a different direction by exploring whether immune system antibodies could be used in drug development.
“Our immune system makes really good antibodies that will clear the pathogen,” she said. “We want to know if we can use the immune system to our advantage. Instead of vaccinating people, we wonder if there is a way we can harvest those antibodies and use those as drugs for the treatment of infections.”
Normally, human antibodies stick to bacteria and trigger signals to the immune system telling it to get to work to clear the invasion. However, Barbier and researchers discovered an antibody produced by mice with the unique property of acting on its own.
“It actually kills the bacteria itself,” Barbier said. “If you just take the antibody and the bacteria and put them in a test tube, the bacteria die. That’s not something we knew antibodies could do and that has really opened our eyes in terms of the potential of antibodies as therapeutics.”
Researchers immunized mice with P. aeruginosa to teach their immune system to recognize the pathogen and make antibodies. They then isolated B cells, the ones that make the antibodies, and then developed methods to produce the antibodies to test them as drugs.
The antibody derived from the immortalized B cells that showed success among the hundreds tested is called WVDC-0496, short for West Virginia Vaccine Development Center.
Expanding on that research, Barbier and her team will assess WVDC-0496 to determine how it destroys bacteria and whether it will work as a therapeutic. The five-year study is supported by a $3.5 million grant from the National Institute of Allergy and Infectious Diseases.
Working with Barbier on the project are Heath Damron, associate professor in the Department of Microbiology, Immunology and Cell Biology in the WVU School of Medicine and director of the Vaccine Development Center; Emel Sen Kilic, a former WVU research assistant professor; and Spencer Dublin, a second-year doctoral student in the biomedical sciences program and a former laboratory technician and undergraduate researcher in Barbier’s lab. Additional students will be recruited to work with the study.
The project evolved from several discoveries made by the researchers over the past 15 years. As a doctoral student, Damron found ways to grow P. aeruginosa in stress conditions that caused it to mimic how it grows in the lungs of people with cystic fibrosis. Later, he and Barbier studied this growth condition. In the past three years, Dr. Jason Kang, a School of Medicine alumnus, continued the work of Damron and Barbier and isolated the antibodies with the novel function of being able to directly kill bacteria.
“We know that if this antibody is administered to mice, it can prevent them from dying of sepsis or pneumonia,” Barbier said. “What we don’t know is whether it could be used in combination with antibiotics or whether it would work against those strains that are extremely resistant to antibiotics.”
Dublin, a first-generation college student from Fairmont, will assist in the project to determine how the antibody functions and has already been testing how it interacts with different antibiotics.
“We actually have observed synergy between our antibody and select antibiotics that increase their function at even lower concentrations,” said Dublin, who will also serve as a mentor to other students who join the lab.
Barbier will partner with researchers from the University of Texas to determine whether the antibody can destroy P. aeruginosa in biofilms — a grouping of bacteria encased in molecules that act as a barrier against immune system antibodies.
“For example, P. aeruginosa causes biofilms in catheters and that’s a reason why some people develop bloodstream infections,” Barbier said. “Once biofilms form, they are very difficult to treat. We want to know if our antibodies can tackle this particularly challenging problem.”
In addition to understanding how WVDC-0496 works to kill bacteria, Barbier said she hopes the study will provide insight into the production of additional antibodies with similar functions against other multidrug-resistant organisms.
Editor’s note: The use of animals in this project was evaluated by the WVU Institutional Animal Care and Use Ethics Committee. WVU is voluntarily accredited by AAALAC, a national peer organization that establishes a global benchmark for animal well-being in science.
