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Synthesis and Evaluation of Pyridine-Based Antibacterial Agents that Inhibit ATP Synthase in Acinetobacter baumannii
Angelina L Dennison1, Armaan Singh1, Toni A Marchlewski1
1Department of Chemistry and Biochemistry, University of North Carolina Asheville, One University Heights, Asheville, North Carolina 28804, United States.
Abstract:
Multidrug resistant Acinetobacter baumannii (MDR AB) is a growing global health threat due to rising infection rates and lack of treatment options. Specifically, like other Gram-negative pathogens, MDR AB employs a suite of robust cellular resistance mechanisms, including reduced penetration of the outer membrane, increased efflux, target modification, and others, that greatly impede antibiotic activity even for antibiotics of last resort like colistin and tigecycline. Bacterial bioenergetics are an under-explored antibiotic target and can be selectively exploited, as demonstrated by the success of the antitubercular drug bedaquiline, which inhibits ATP synthase in Mycobacterium tuberculosis. While work has been done to expand the success of bedaquiline to Gram-negative pathogens like AB through quinoline derivation, modifications to the quinoline core have been minimal. Herein, we report the synthesis and evaluation of a library of trisubstituted pyridines for their ability to inhibit AB ATP synthase and act as antibacterial agents against both susceptible and MDR AB clinical isolates. From this work, four lead compounds were developed that are highly potent and selective AB ATP synthase inhibitors and act as antibiotics against MDR AB. Additionally, each of the lead compounds were found to act synergistically with colistin against AB in bacterial culture, which demonstrates the further potential of this class to be developed into potent antibiotics.
Insights
New pyridine compounds show promise in combating multidrug-resistant Acinetobacter baumannii (MDR AB). These compounds inhibit bacterial ATP synthase, offering a novel strategy against infections resistant to current antibiotics and potentiating existing treatments.
Area of Science:
- Microbiology
- Medicinal Chemistry
- Drug Discovery
Background:
- Multidrug-resistant Acinetobacter baumannii (MDR AB) presents a significant global health challenge due to limited effective treatment options.
- MDR AB possesses intrinsic resistance mechanisms, including reduced outer membrane penetration and enhanced efflux pumps, complicating antibiotic efficacy.
- Bacterial bioenergetics, specifically ATP synthase, represent a promising, yet underexplored, target for novel antibacterial agents.
Purpose of the Study:
- To synthesize and evaluate a library of trisubstituted pyridine derivatives as inhibitors of Acinetobacter baumannii ATP synthase.
- To assess the antibacterial activity of these pyridine compounds against both susceptible and multidrug-resistant clinical isolates of Acinetobacter baumannii.
- To explore the potential synergistic effects of these novel compounds with existing antibiotics like colistin.
Main Methods:
- Synthesis of a diverse library of trisubstituted pyridine compounds.
- Biochemical assays to determine ATP synthase inhibition potency and selectivity.
- In vitro antibacterial activity testing against a panel of Acinetobacter baumannii clinical isolates, including MDR strains.
- Checkerboard assays to evaluate synergistic interactions with colistin.
Main Results:
- Identification of four lead trisubstituted pyridine compounds demonstrating high potency and selectivity as Acinetobacter baumannii ATP synthase inhibitors.
- Demonstration of significant antibacterial activity of these lead compounds against multidrug-resistant Acinetobacter baumannii clinical isolates.
- Evidence of synergistic activity between the lead pyridine compounds and colistin in bacterial culture, enhancing overall efficacy.
Conclusions:
- Trisubstituted pyridines represent a promising new class of compounds targeting bacterial bioenergetics.
- These compounds offer a viable therapeutic strategy against challenging MDR AB infections.
- The observed synergy with colistin suggests potential for combination therapies to overcome antibiotic resistance.
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