Augmenting the Activity of Macrolide Adjuvants against Acinetobacter baumannii
Veronica B Hubble1, Kyle R Bartholomew2, Alexander W Weig1
1Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, Indiana 46556, United States.
Abstract:
Approximately 1.7 million Americans develop hospital associated infections each year, resulting in more than 98,000 deaths. One of the main contributors to such infections is the Gram-negative pathogen Acinetobacter baumannii. Recently, it was reported that aryl 2-aminoimidazole (2-AI) compounds potentiate macrolide antibiotics against a highly virulent strain of A. baumannii, AB5075. The two lead compounds in that report increased clarithromycin (CLR) potency against AB5075 by 16-fold, lowering the minimum inhibitory concentration (MIC) from 32 to 2 μg/mL at a concentration of 10 μM. Herein, we report a structure-activity relationship study of a panel of derivatives structurally inspired by the previously reported aryl 2-AI leads. Substitutions around the core phenyl ring yielded a lead that potentiates clarithromycin by 64- and 32-fold against AB5075 at 10 and 7.5 μM, exceeding the dose response of the original lead. Additional probing of the amide linker led to the discovery of two urea containing adjuvants that suppressed clarithromycin resistance in AB5075 by 64- and 128-fold at 7.5 μM. Finally, the originally reported adjuvant was tested for its ability to suppress the evolution of resistance to clarithromycin over the course of nine consecutive days. At 30 μM, the parent compound reduced the CLR MIC from 512 to 2 μg/mL, demonstrating that the original lead remained active against a more CLR resistant strain of AB5075.
Insights
New aryl 2-aminoimidazole (2-AI) compounds enhance macrolide antibiotic effectiveness against Acinetobacter baumannii. These novel agents significantly boost clarithromycin potency and suppress resistance development in hospital-associated infections.
Area of Science:
- Microbiology
- Medicinal Chemistry
- Infectious Diseases
Background:
- Hospital-associated infections (HAIs) are a major public health concern, with Gram-negative pathogens like Acinetobacter baumannii being significant contributors.
- Acinetobacter baumannii infections are notoriously difficult to treat due to increasing antibiotic resistance.
- Previous research identified aryl 2-aminoimidazole (2-AI) compounds as potentiators of macrolide antibiotics against A. baumannii.
Purpose of the Study:
- To conduct a structure-activity relationship (SAR) study of aryl 2-AI derivatives to identify improved potentiators of macrolide antibiotics.
- To discover novel adjuvant compounds that can suppress antibiotic resistance in A. baumannii.
- To evaluate the ability of a lead adjuvant to prevent the evolution of clarithromycin resistance.
Main Methods:
- Synthesis and testing of a panel of aryl 2-AI derivatives.
- Determination of minimum inhibitory concentrations (MICs) for clarithromycin (CLR) in combination with various 2-AI compounds against Acinetobacter baumannii AB5075.
- Assessment of adjuvant activity at different concentrations and evaluation of resistance suppression over time.
Main Results:
- A novel aryl 2-AI derivative demonstrated enhanced potentiation of clarithromycin (CLR) against A. baumannii AB5075, achieving 64-fold and 32-fold increases in potency at 10 μM and 7.5 μM, respectively.
- Two new urea-containing adjuvants were discovered, suppressing CLR resistance by 64-fold and 128-fold at 7.5 μM.
- The original lead adjuvant effectively reduced the CLR MIC from 512 to 2 μg/mL against a CLR-resistant strain, indicating sustained activity.
Conclusions:
- Structural modifications of aryl 2-AI compounds can lead to significantly improved macrolide antibiotic potentiators.
- Novel urea-containing adjuvants show promise in overcoming clarithromycin resistance in Acinetobacter baumannii.
- These findings offer potential new strategies for combating challenging Gram-negative bacterial infections and mitigating antibiotic resistance.
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