Topical drugs have quite a few advantages to tout. They’re noninvasive, treat directly at the site they’re needed, and are easily administered by patients. However, topical drugs need frequent reapplication because they don’t stay long on the skin. This can lead to patients missing doses or stopping the medication all together.
To solve the challenge of frequent dosing, Mark Prausnitz’s group from the Georgia Institute of Technology recently explored how to engineer bacteria to produce drugs directly on the skin. In a proof-of-concept study, they found that when applied daily or every other day, their bacterial drug delivery system can stay on the skin much longer than current topicals (1).
Their organism of choice for their delivery system was Bacillus subtilis. “What was important to us is the fact that it's been identified on the skin,” said Veronica Montgomery, a coauthor of the paper who is now a postdoctoral researcher at Sandia National Laboratories. “It's a lot easier to work with than a lot of the organisms that are more commonly associated with the skin. It's very genetically tractable and has a lot of history of use in humans.”
Montgomery began with B. subtilis that expressed green fluorescent protein (GFP). By measuring the amount of fluorescence, the researchers used these bacteria as a model for topical therapeutic protein expression and delivery. Through a combination of computational models that predict bacterial population dynamics on the skin and experimental models, Montgomery found that the bacteria persisted and produced GFP for four days on ex vivo pig skin, two days in human skin cultures, and up to three days on the skin of living mice.
Creating a bacterial drug delivery system is more than just adding bacteria to the skin and seeing if it persists. It also involves tweaking growth conditions and nutrient sources to optimize the bacteria’s time on the skin. Montgomery found that adding B. subtilis’s preferred carbon source extended survival time and GFP production on pig skin to five days.
“Trying to use microbes for drug delivery to the skin is really challenging because you already have the existing skin microbiome, which adds a lot of competition,” said Montgomery. Furthermore, engineered bacteria are going to have more of a metabolic burden than native skin bacteria, which hurts their ability to compete, she explained.
“It's a really early look at how to deliver these therapeutics to the skin,” said Ava Vargason, a pharmaceutical scientist at the University of North Carolina at Chapel Hill who was not involved in this study. “They hit on some really important challenges like the availability of nutrients for an externally applied bacteria [and] the competition with native bacteria.”
Topical microbial-based protein delivery systems are beginning to progress through nonclinical development and clinical trials. Scientists at Azitra are engineering Staphylococcus epidermidis for protein delivery to treat skin conditions like Netherton syndrome and ichthyosis vulgaris, while researchers at Ilya Pharma are developing Limosilactobacillus reuteri to facilitate wound healing (2).
While it might take time, Montgomery sees the potential for a microbial-based delivery system to deliver not only therapeutic drugs but also produce sunscreen or mosquito repellent directly on the skin.
“I'm excited that there's more interest in this field. It's relatively new,” Vargason said.
References
- Montgomery, V.A. et al. Feasibility of engineered Bacillus subtilis for use as a microbiome-based topical drug delivery platform. Bioeng Transl Med 2024, e10645 (2024).
- Öhnstedt, E. et al. Engineered bacteria to accelerate wound healing: an adaptive, randomised, double-blind, placebo-controlled, first-in-human phase 1 trial. eClinicalMedicine 60, 102014 (2023).
