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Discovery of an adjuvant that resensitizes polymyxin B-resistant bacteria
Michael Mahdavi1, Brandon L Findlay2
1Department of Chemistry and Biochemistry, Concordia University, Montréal, Québec, Canada.
Abstract:
Infections caused by antibiotic-resistant bacteria are a major threat to health, increasing mortality rates and straining health systems worldwide. Adjuvants targeted to beta-lactamase function are able to resensitize bacteria to beta-lactam antibiotics, but there is comparatively little research into the use of adjuvants against other resistance phenotypes. In this study, we performed a high-throughput screen of 74 natural products to identify adjuvants that synergized with antibiotics to eradicate resistant Gram-negative bacteria. From this, we identified six adjuvant hits which restored growth inhibition when combined with the relevant antibiotic, and pursued a lead candidate, perforone, which possessed selective adjuvant activity in combination with polymyxin B against polymyxin-resistant Escherichia coli cells. These results suggest that pairing adjuvants with antibiotics could be a useful general intervention against resistant bacteria, helping to mitigate the effects of antimicrobial resistance.
Insights
This study screened natural products for adjuvants that enhance antibiotic effectiveness against resistant bacteria. A lead compound, perforone, showed promise in combination with polymyxin B against resistant E. coli.
Area of Science:
- Microbiology and Infectious Diseases
- Drug Discovery and Development
- Antimicrobial Resistance Research
Background:
- Antibiotic-resistant bacterial infections pose a significant global health threat, increasing mortality and healthcare burdens.
- While adjuvants exist for beta-lactamase resistance, research into adjuvants for other resistance mechanisms is limited.
- Novel strategies are urgently needed to combat the growing challenge of antimicrobial resistance.
Purpose of the Study:
- To identify natural product-derived adjuvants that synergize with antibiotics against resistant Gram-negative bacteria.
- To evaluate the potential of identified adjuvants in overcoming specific antibiotic resistance phenotypes.
- To explore novel therapeutic approaches for mitigating the impact of antimicrobial resistance.
Main Methods:
- Conducted a high-throughput screen of 74 natural products to identify synergistic adjuvant-antibiotic combinations.
- Tested identified adjuvant hits for their ability to restore antibiotic efficacy against resistant bacterial strains.
- Focused on a lead candidate, perforone, for its adjuvant activity in combination with polymyxin B against polymyxin-resistant Escherichia coli.
Main Results:
- Identified six natural products exhibiting adjuvant activity, restoring antibiotic-mediated growth inhibition.
- Perforone demonstrated selective adjuvant activity, enhancing the efficacy of polymyxin B against polymyxin-resistant E. coli.
- The study highlights the potential of natural products as sources for novel antimicrobial adjuvants.
Conclusions:
- Pairing adjuvants with existing antibiotics represents a promising strategy to combat resistant bacteria.
- Natural products can serve as valuable sources for discovering effective adjuvants against diverse resistance mechanisms.
- Further research into adjuvant-antibiotic combinations could provide a vital tool in the fight against antimicrobial resistance.
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