Cross-resistance to 14-, 15- and 16-membered ring macrolides in Salmonella and Campylobacter
Ruby Singh1, Sampa Mukherjee2, Lucas B Harrision2
1Center for Veterinary Medicine, Office of New Animal Drug Evaluation, U.S. Food and Drug Administration, Rockville, MD, USA.
Objectives:
This study aimed to gain a better understanding of how resistance determinants in Salmonella and Campylobacter contribute to 14-, 15- and 16-membered ring macrolide resistance phenotypes.
Methods:
A total of 126 azithromycin-resistant (AziR) and -susceptible (AziS) [Salmonella (n = 45) and Campylobacter (n = 81)] isolates were selected for antimicrobial susceptibility testing (AST) and WGS.
Results:
Seven functional macrolide resistance determinants, including erm(42), mef(C), mph(A), mph(E), mph(G), msr(E) and one point mutation (acrB_R717L) were previously identified in AziRSalmonella. These determinants resulted in an 8- and 16-fold 15-membered ring gamithromycin and azithromycin MIC50 increase, respectively, compared with AziS isolates, with a maximum MIC increase of up to 256. The same isolates also exhibited up to a 32-fold 14-membered ring erythromycin MIC50 increase. Salmonella with erm(42) or acrB_R717L showed up to 128-fold 16-membered ring macrolide tildipirosin MIC increase, compared with isolates that were susceptible or carrying other macrolide resistance genes. In Campylobacter, all AziR isolates had an MIC50 ranging from 32 to 4096 mg/L of the various membered ring macrolides, whereases all susceptible Campylobacter isolates had significantly lower MIC50 values, ranging from 0.25 to 4 mg/L. The MIC50 of the various ring macrolides for AziRCampylobacter isolates was 16- to 4096-fold higher when compared with AziSCampylobacter.
Conclusions:
Our study has revealed that the function of macrolide resistance genes in Salmonella can be associated with specific macrolide ring structures, whereas the single 23S rRNA mutation in Campylobacter results in significantly elevated MICs of all macrolides. for the various ring macrolides.
Insights
Macrolide resistance genes in Salmonella are linked to specific ring structures, while a single mutation in Campylobacter significantly increases resistance to all macrolides. This impacts antimicrobial susceptibility testing and treatment strategies.
Area of Science:
- Microbiology
- Molecular Biology
- Antimicrobial Resistance
Background:
- Macrolide antibiotics are crucial for treating bacterial infections.
- Emergence of macrolide resistance in bacterial pathogens like Salmonella and Campylobacter poses a significant public health threat.
- Understanding the genetic basis of macrolide resistance is essential for developing effective treatment strategies.
Purpose of the Study:
- To investigate the contribution of specific resistance determinants to macrolide resistance phenotypes in Salmonella and Campylobacter.
- To analyze the impact of different macrolide ring structures on resistance mechanisms.
- To identify genetic factors associated with azithromycin resistance in these bacteria.
Main Methods:
- Antimicrobial susceptibility testing (AST) was performed on 126 azithromycin-resistant and -susceptible Salmonella and Campylobacter isolates.
- Whole-genome sequencing (WGS) was employed to identify resistance determinants and mutations.
- Minimum Inhibitory Concentration (MIC) values were determined for various macrolides.
Main Results:
- Seven functional macrolide resistance determinants and one point mutation (acrB_R717L) were identified in azithromycin-resistant Salmonella.
- These determinants conferred increased resistance to 14-, 15-, and 16-membered ring macrolides, with MIC increases up to 256-fold.
- In Campylobacter, azithromycin-resistant isolates exhibited significantly higher MICs (16- to 4096-fold) for various macrolides compared to susceptible isolates, primarily due to a 23S rRNA mutation.
Conclusions:
- Macrolide resistance gene function in Salmonella is associated with specific macrolide ring structures.
- A single 23S rRNA mutation in Campylobacter leads to broad-spectrum macrolide resistance.
- These findings highlight distinct resistance mechanisms in Salmonella and Campylobacter, informing antimicrobial stewardship.
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