Impaired Fitness and Transmission of Macrolide-Resistant Campylobacter jejuni in Its Natural Host

Abstract

Campylobacter jejuni is a major zoonotic pathogen transmitted to humans via the food chain and is prevalent in chickens, a natural reservoir for this pathogenic organism. Due to the importance of macrolide antibiotics in clinical therapy of human campylobacteriosis, development of macrolide resistance in Campylobacter has become a concern for public health. To facilitate the control of macrolide-resistant Campylobacter, it is necessary to understand if macrolide resistance affects the fitness and transmission of Campylobacter in its natural host. In this study we conducted pairwise competitions and comingling experiments in chickens using clonally related and isogenic C. jejuni strains, which are either susceptible or resistant to erythromycin (Ery). In every competition pair, Ery-resistant (Ery r ) Campylobacter was consistently outcompeted by the Ery-susceptible (Ery s ) strain. In the comingling experiments, Ery r Campylobacter failed to transmit to chickens precolonized by Ery s Campylobacter, while isogenic Ery s Campylobacter was able to transmit to and establish dominance in chickens precolonized by Ery r Campylobacter. The fitness disadvantage was linked to the resistance-conferring mutations in the 23S rRNA. These findings clearly indicate that acquisition of macrolide resistance impairs the fitness and transmission of Campylobacter in chickens, suggesting that the prevalence of macrolide-resistant C. jejuni will likely decrease in the absence of antibiotic selection pressure.

Mutational and Transcriptomic Changes Involved in the Development of Macrolide Resistance in Campylobacter jejuni

“…Third, a large number of genes involved in the heat shock response, motility, and energy metabolism were significantly downregulated in the macrolideresistant mutants, suggesting that the development of macrolide resistance in C. jejuni profoundly impacts Campylobacter physiology and may result in a growth burden and fitness cost. Indeed, several recent studies found that macrolide-resistant Campylobacter shows a significant fitness cost in vitro and in vivo and is outcompeted by susceptible Campylobacter in the chicken host in the absence of antibiotic selection pressure (41)(42)(43)(44).…”

The Challenge of Efflux-Mediated Antibiotic Resistance in Gram-Negative Bacteria

“…It should be noted that the multiple-stepwise-selection approach could yield pleiotropic mutations, thus underestimating the importance of the CmeABC-overproducing mutants that also possessed ϳ200 up-or downregulated genes (including the upregulation of genes encoding an SMR pump [Cj1173] and two MFS pumps [CmeG and Cj0035c]), and some of these changes may affect physiology and metabolism (668). The latter offers an explanation regarding the growth burdens and fitness cost of macrolide-resistant campylobacters reported by the groups of Zhang and Yuan (669)(670)(671). Additional pumps that are independent of CmeABC and CmeEFG also likely mediate MDR (16) but remain to be further studied.…”

Use of Collateral Sensitivity Networks to Design Drug Cycling Protocols That Avoid Resistance Development

“…However, the spread of resistant bacterial strains still occurs even though resistance can be costly in terms of bacterial fitness (23)(24)(25). In addition, not all resistance carries fitness cost (26,27), and the fitness cost can be ameliorated by compensatory mutations (22,28).…”