Overcoming Bacterial Obstacles: Enhanced Treatment for Chronic Wound Infections

The accompanying image depicts the process of ultrasound-mediated drug delivery into a wound infected with biofilm. Credit: Ella Marushchenko

Researchers have come up with an innovative approach for more effective drug delivery in the case of chronic wound infections.

Chronic wounds, the kind that persistently remain open or damage tissue without healing properly, present a considerable treatment challenge due to bacterial infections, notably Staphylococcus aureus, or S. aureus. When such bacteria exhibit antibiotic resistance, such as in the case of methicillin-resistant S. aureus (MRSA), a common cause of severe infections in hospitals, the situation becomes even more problematic.

Sarah Rowe-Conlon, Ph.D. Credit: UNC Department of Microbiology and Immunology

S. aureus, in order to shield itself from the human immune system and other potential dangers, can congregate to create a slick and gooey barrier known as a biofilm. This biofilm barrier is so formidable that neither immune cells nor antibiotics can break through to neutralize the harmful bacteria.

A new method has been devised by scientists at the UNC School of Medicine and the UNC-NC State Joint Department of Biomedical Engineering. This method combines palmitoleic acid, gentamicin, and non-invasive ultrasound to facilitate more efficient drug delivery to chronic wounds infected with S. aureus.

By employing this novel strategy, researchers managed to reduce MRSA infection in diabetic mice’s wounds by 94%. They even managed to entirely sterilize the wounds in several mice, while substantially lessening the bacterial load in others. The study was published in Cell Chemical Biology.

Senior author Sarah Rowe-Conlon, Ph.D., a research associate professor in the Department of Microbiology and Immunology, stated that “incomplete clearance of bacteria from chronic wounds exposes the patient to high risks of recurring infections or secondary infections. This therapeutic strategy has the potential to enhance patient outcomes and decrease chronic wound infection relapse. We’re excited about the prospect of applying this to clinical scenarios, which is currently our main focus.”

Biofilms pose a physical obstruction to several types of antibiotics. Virginie Papadopoulou, Ph.D., a research assistant professor in the UNC-NCSU Joint Department of Biomedical Engineering, wondered if non-invasive cavitation-enhanced ultrasound could cause enough disruption to form open spaces in the biofilm, thereby facilitating drug delivery.

Paul Dayton, Ph.D. Credit: UNC-NCSU Joint Department of Biomedical Engineering

Phase change contrast agents (PCCAs) are liquid droplets that can be activated by ultrasound and are applied directly to the wound. When an ultrasound transducer is aimed at the wound and activated, the liquid within the droplets expands, forming gas-filled microbubbles that move rapidly.

These oscillating microbubbles disturb the biofilm both by physically breaking it down and enhancing fluid flow. The result is an improved drug permeation through the biofilm and an increased bacterial biofilm extermination efficiency.

Paul Dayton, the William R. Kenan Jr. Distinguished Professor and Department Chair of the UNC-NCSU Joint Department of Biomedical Engineering, said, “Microbubbles and phase change contrast agents magnify the effect of ultrasound energy locally, allowing us to specifically target wounds and body areas for therapeutic outcomes beyond the reach of standard ultrasound. We hope to use similar technologies to deliver chemotherapy locally to stubborn tumors or introduce new genetic material into damaged cells.”

Bacterial cells become trapped inside the biofilm, leading to limited access to nutrients and oxygen. Consequently, they transition into a dormant state to conserve resources and energy. These so-called persister cells exhibit extreme resistance to antibiotics.

Researchers selected gentamicin, a topical antibiotic generally ineffective against S. aureus due to widespread antibiotic resistance and poor activity against persister cells, and introduced an innovative antibiotic adjuvant, palmitoleic acid, to their models.

Palmitoleic acid is an unsaturated fatty acid naturally produced by the human body that possesses potent antibacterial properties. This fatty acid embeds itself into the bacterial cell membrane, aiding the successful entry of antibiotics into S. aureus cells and killing persister cells, thereby reversing antibiotic resistance.

The team is highly optimistic about this new non-invasive, topical approach because it could provide researchers and doctors with additional tools to fight antibiotic resistance and reduce the serious side effects of oral antibiotics.

Systemic antibiotics, such as oral or IV types, are generally effective but come with considerable risks, including toxicity, destruction of gut microflora, and C. difficile infection,” explained Rowe-Conlon. “Using this system, we can enhance the effectiveness of topical drugs, allowing them to be directly applied to the infection site in high concentrations, without the risks tied to systemic delivery.”

Reference: “Overcoming biological barriers to improve treatment of a Staphylococcus aureus wound infection” by Virginie Papadopoulou, Ashelyn E. Sidders, Kuan-Yi Lu, Amanda Z. Velez, Phillip G. Durham, Duyen T. Bui, Michelle Angeles-Solano, Paul A. Dayton and Sarah E. Rowe, 5 May 2023, Cell Chemical Biology.
DOI: 10.1016/j.chembiol.2023.04.009

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• Chronic Wounds
• Staphylococcus aureus Infections
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• Cell Chemical Biology Journal
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