The rising rate of antibiotic resistance represents a major challenge for modern medicine. The repeated use of antibiotics leads to the emergence of increasingly resistant bacteria, compromising the drugs’ efficacy and limiting treatment options. Brandon Findlay, associate professor at Concordia University, heads a biochemistry and biology research group that’s delving into the phenomenon. The goal is to anticipate bacterial evolution in clinical settings and better understand resistance mechanisms.
With that in mind, Findlay and his team developed the innovative Soft Agar Gradient Evolution (SAGE) platform to observe in vitro and in fast time the increase in resistance of bacteria in culture media containing different antibiotic gradients. As they tracked this evolution, the experts found that the bacteria that had become resistant to a specific antibiotic were slower to adapt to a new one. This observation suggests that, in clinical settings, sequential therapies that rely on the use of one antibiotic after another could remain effective even when resistance has set in. Identifying the most appropriate antibiotics could therefore help clinicians prescribe sequential therapies that are less prone to resistance.
The experiments also revealed that resistance to one antibiotic can bring about collateral sensitivity: increased vulnerability to other compounds. The discovery led to the identification of the perforone molecule, which restores the sensitivity of bacteria to the last-resort antibiotic polymyxin B. In collaboration with other researchers, the team has now begun targeting and confirming new potential antibiotics including a formulation of the GL 13K antimicrobial peptide to fight the Pseudomonas aeruginosa pathogen, which is challenging to treat.
The research establishes that current antibiotic treatments can be used more effectively, paving the way for promising new therapies to fight bacterial infections.
References
Chowdhury F.R. et Findlay B. L. (2023) Fitness Costs of Antibiotic Resistance Impede the Evolution of Resistance to Other Antibiotics. ACS Infectious Diseases, 9(10), 1834-1845 https://doi.org/10.1021/acsinfecdis.3c00156
Ghaddar, N., Hashemidahaj, M. et Findlay, B.L. (2018) Access to high-impact mutations constrains the evolution of antibiotic resistance in soft agar. Sci Rep 8, 17023. https://doi.org/10.1038/s41598-018-34911-9
Mahdavi, M., Findlay, B.L. (2024) Discovery of an adjuvant that resensitizes polymyxin B-resistant bacteria. Bioorganic & Medicinal Chemistry, 97,117541,
https://doi.org/10.1016/j.bmc.2023.117541.
Ali, D. A., Dominguez Mercado, L., Findlay, B.L., Badia, A., DeWolf, C. (2023) Opposites Attract: Electrostatically Driven Loading of Antimicrobial Peptides into Phytoglycogen Nanocarriers. Langmuir, 39 (1), 53-63 https://doi.org/10.1021/acs.langmuir.2c01794.