Researchers at Case Western Reserve University School of Medicine have received a $3.34 million grant from the National Institutes of Health (NIH) to develop a new strategy to sensitize Burkholderia multivorans — a common pathogen in patients with lung diseases like cystic fibrosis (CF) — to the action of antibiotics.
Colonization by the opportunistic bacterium Burkholderia multivorans can result in long-lasting chronic infections in CF patients. The pathogen is resistant to a broad range of antibiotics, and infections can cause severe disease and poor prognosis in patients.
Previous studies by the research team showed that Burkholderia multivorans can reinforce its protective cell walls and, as a result, prevent antibiotics from entering the organism. That is why the Case Reserve team now wants to better understand the bacterial mechanisms behind its antibiotic resistance, and to find ways to block them.
“My goal is to disable the wall structures, allowing antibiotics to penetrate the bacteria and render it ineffective,” Edward W. Yu, PhD, said in a press release. Yu is a professor of pharmacology at Case Western and principal investigator of the project.
The researchers previously found that by transporting an unusual type of lipid compound called hopanoids from the inner to the outer cell membranes (which separates the interior of the cell from the outside), the bacterium B. multivorans can strengthen its cell wall. The increased cell wall rigidity subsequently acts as a barrier against antibiotics, blocking them from entering the cell.
“Our goal is to surmount the B. multivorans wall and enable antibiotics currently ineffective against the pathogen to be re-introduced into use in patients with serious infections,” Yu said.
The researchers found preliminary evidence suggesting that two proteins — HpnN and HpnM — are involved in the transport of hopanoids.
With the new grant, the team intends to identify new peptides (short chains of amino acids) that bind the proteins and block their function. This protein inhibition could thus weaken the cell wall of B. multivorans and, in combination with existing antibiotics, successfully treat an infection.
If the approach is successful, researchers aim to extend the findings to test the combination in mouse models.
“These peptides also represent a novel approach to the treatment of drug-resistant infections that may potentially enhance the immune response,” said Robert A. Bonomo, MD, professor of medicine, pharmacology, molecular biology and microbiology at Case Western Reserve University.
“If successful, our strategy could be transferred to other bacterial pathogens such as E. coli, Neisseria, Pseudomonas and Acinetobacter infections, which would provide a way to treat these infections with existing antibiotics,” Bonomo concluded.
The research project is funded by the National Institute of Allergy and Infectious Disease, part of the NIH.