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Methods to Inhibit Bacterial Pyomelanin Production and Determine the Corresponding Increase in Sensitivity to Oxidative Stress
Published on: August 31, 2015
Discovery of a novel polymyxin adjuvant against multidrug-resistant gram-negative bacteria through oxidative stress
Taotao Lu1, Hongguang Han2, Chaohui Wu2
1State Key Laboratory of Bioreactor Engineering, Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism, Frontiers Science Center for Materiobiology and Dynamic Chemistry, Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China.
Abstract:
Antibiotic adjuvants offer a promising strategy for restoring antibiotic sensitivity, expanding antibacterial spectra, and reducing required dosages. Previously, compound 15 was identified as a potential adjuvant for Polymyxin B (PB) against multidrug-resistant (MDR) Pseudomonas aeruginosa DK2; however, its clinical utility was hindered by high cytotoxicity, uncertain in vivo efficacy, and an unclear synergetic mechanism. To address these challenges, we synthesized and evaluated a series of novel benzamide derivatives, with A22 emerging as a particularly promising candidate. A22 demonstrated potent synergistic activity to PB, minimal cytotoxicity, improved water solubility, and broad-spectrum synergism of polymyxins against various clinically isolated MDR Gram-negative strains. In vivo studies using Caenorhabditis elegans and mouse models further confirmed the efficacy of A22. Moreover, A22 effectively suppressed the development of PB resistance in Pseudomonas aeruginosa DK2. Mechanistic investigations revealed that A22 enhances polymyxins activity by inducing reactive oxygen species production, reducing ATP levels, increasing NOX activity, and inhibiting biofilm formation, leading to bacterial death. These findings position A22 as a highly promising candidate for the development of polymyxin adjuvants, offering a robust approach to combating MDR Gram-negative bacterial infections.
Insights
A novel compound, A22, acts as a potent antibiotic adjuvant, enhancing Polymyxin B
Area of Science:
- Microbiology
- Pharmacology
- Medicinal Chemistry
Background:
- Antibiotic adjuvants can restore sensitivity to existing antibiotics.
- Previous adjuvant candidate (compound 15) showed high cytotoxicity and unclear efficacy.
- Multidrug-resistant (MDR) Gram-negative bacterial infections pose a significant clinical challenge.
Purpose of the Study:
- To synthesize and evaluate novel benzamide derivatives as potential antibiotic adjuvants.
- To address the limitations of previous adjuvant candidates.
- To develop effective strategies against MDR Gram-negative bacteria.
Main Methods:
- Synthesis and evaluation of novel benzamide derivatives.
- Testing synergistic activity with Polymyxin B (PB) against MDR bacteria.
- In vitro and in vivo efficacy studies (C. elegans, mouse models).
- Mechanistic investigations into A22's mode of action.
Main Results:
- A22 demonstrated potent synergistic activity with PB against MDR Gram-negative strains.
- A22 exhibited minimal cytotoxicity, improved solubility, and broad-spectrum synergism.
- In vivo studies confirmed A22's efficacy and its ability to suppress PB resistance.
- A22 enhances PB activity by inducing ROS, reducing ATP, increasing NOX activity, and inhibiting biofilm.
Conclusions:
- A22 is a highly promising candidate for developing polymyxin adjuvants.
- A22 offers a robust approach to combatting MDR Gram-negative bacterial infections.
- The findings support A22's potential clinical utility in overcoming antibiotic resistance.
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