Resistance Mechanisms to DNA Gyrase Inhibitors in Bacteria
Author Information
Author(s): Semen A. Leyn, James E. Kent, Jaime E. Zlamal, Marinela L. Elane, Maarten Vercruysse, Andrei L. Osterman
Primary Institution: Sanford Burnham Prebys Medical Discovery Institute
Hypothesis
What are the evolutionary dynamics of resistance acquisition against DNA gyrase/topoisomerase inhibitors in gram-negative pathogens?
Conclusion
The study found that resistance to the TriBE inhibitor GP6 in E. coli and A. baumannii is primarily driven by mutations in the GyrB ATP-binding site and efflux pump upregulation.
Supporting Evidence
- Resistance to GP6 was driven by mutations in the GyrB ATP-binding site.
- Efflux pump upregulation was a significant factor in resistance development.
- Distinct evolutionary trajectories were observed for GP6 compared to ciprofloxacin.
- Most GP6-resistant isolates showed cross-resistance to ciprofloxacin.
- Experimental evolution was conducted using a morbidostat to simulate continuous drug pressure.
- Whole genome sequencing provided insights into the mutational landscape of resistance.
- Different mutational events were identified in E. coli and A. baumannii.
- Findings suggest that GP6 may be effective against ciprofloxacin-resistant bacteria.
Takeaway
Bacteria can become resistant to new antibiotics by changing their DNA or by pumping the drugs out, and this study looked at how that happens with a specific antibiotic.
Methodology
The study used a morbidostat for continuous culturing and whole genome sequencing to analyze evolving bacterial populations.
Limitations
The study's findings may not fully represent in vivo conditions as it was conducted in vitro.
Digital Object Identifier (DOI)
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