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Updated: Jun 23, 2025
Quantification of Plasmid-Mediated Antibiotic Resistance in an Experimental Evolution Approach
Published on: December 14, 2019
A small molecule that inhibits the evolution of antibiotic resistance
Juan Carvajal-Garcia1, Harrison Bracey1, Anna E Johnson1
1Department of Biochemistry, Vanderbilt University, Nashville, TN 37232, USA.
Abstract:
Antibiotic resistance rapidly develops against almost all available therapeutics. Therefore, searching for new antibiotics to overcome the problem of antibiotic resistance alone is insufficient. Given that antibiotic resistance can be driven by mutagenesis, an avenue for preventing it is the inhibition of mutagenic processes. We previously showed that the DNA translocase Mfd is mutagenic and accelerates antibiotic resistance development. Here, we present our discovery of a small molecule that inhibits Mfd-dependent mutagenesis, ARM-1 (anti-resistance molecule 1). We found ARM-1 using a high-throughput, small molecule, in vivo screen. Using biochemical assays, we characterized the mechanism by which ARM-1 inhibits Mfd. Critically, we found that ARM-1 reduces mutagenesis and significantly delays antibiotic resistance development across highly divergent bacterial pathogens. These results demonstrate that the mutagenic proteins accelerating evolution can be directly inhibited. Furthermore, our findings suggest that Mfd inhibition, alongside antibiotics, is a potentially effective approach for prevention of antibiotic resistance development during treatment of infections.
Insights
Scientists discovered ARM-1, a molecule that inhibits the mutagenic protein Mfd. This discovery offers a new strategy to prevent antibiotic resistance by targeting mutagenesis, not just bacteria.
Area of Science:
- Microbiology
- Molecular Biology
- Drug Discovery
Background:
- Antibiotic resistance is a growing global health threat, necessitating novel strategies beyond traditional antibiotic development.
- Mutagenesis, the process of genetic mutation, can accelerate the development of antibiotic resistance.
- The DNA translocase Mfd has been identified as a mutagenic protein that promotes antibiotic resistance.
Purpose of the Study:
- To discover and characterize a small molecule inhibitor of Mfd-dependent mutagenesis.
- To evaluate the efficacy of this inhibitor in preventing antibiotic resistance development in bacterial pathogens.
Main Methods:
- High-throughput small molecule screening in vivo to identify inhibitors of Mfd.
- Biochemical assays to elucidate the mechanism of inhibition.
- Testing the inhibitor's effect on mutagenesis and antibiotic resistance development in diverse bacterial pathogens.
Main Results:
- Discovery of ARM-1 (anti-resistance molecule 1), a novel small molecule inhibitor of Mfd.
- ARM-1 was shown to biochemically inhibit Mfd-dependent mutagenesis.
- ARM-1 significantly reduced mutagenesis and delayed antibiotic resistance development in multiple bacterial species.
Conclusions:
- Inhibiting mutagenic proteins like Mfd is a viable strategy to combat antibiotic resistance.
- ARM-1 represents a promising therapeutic lead for preventing antibiotic resistance.
- Combining Mfd inhibitors with antibiotics could be an effective approach for treating infections and preventing resistance.
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