Collateral sensitivity in clinical mecillinam resistant isolates of Escherichia coli

Abstract

Background The rapid increase in antimicrobial resistance (AMR) has become a major threat to the successful management of infectious diseases. To counteract this global threat, development of novel treatment strategies is essential. A promising strategy may be exploiting collateral sensitivity; a phenomenon that occurs when a microorganism that has developed resistance to one antimicrobial agent, exhibits increased susceptibility to another antimicrobial agent. In order to develop novel treatment strategies and prevent further resistance development, we aimed to explore the generality of the concept of collateral sensitivity in clinical urinary tract isolates of E. coli. Furthermore, we wanted to investigate the underlying mechanisms of collateral sensitivity. Methods We evolved resistance to mecillinam in a collection of clinical isolates of E. coli. Ten were selected for further determination of possible collateral sensitivity and cross-resistance networks. The IC90-assay with micro broth dilution was used for this purpose, which we tested for eight different antimicrobial agents. The results were displayed in heat maps and graphs showing the distribution of AMR to various agents. PCR and DNA sequencing were performed for the mrdA gene to detect mutations that may confer mecillinam resistance. Results According to our results both collateral sensitivity and cross-resistance occurred in mecillinam resistant isolates. Chloramphenicol presented the highest tendency of collateral sensitivity, while ciprofloxacin presented the highest tendency of cross-resistance. In general, a substantial tendency for collateral sensitivity frequently appeared compared to cross-resistance. Moreover, 13 synonymous point mutations were observed in the mrdA gene, leading to no alteration in the amino acid sequence. Conclusion Based on our in vitro results, we suggest mecillinam could be a good candidate to be employed as the first drug of choice for UTIs caused by E. coli. Mecillinam resistant isolates exhibited a clear tendency for collateral sensitivity, which we believe would occur on the population level as well. Further investigations of the underlying mechanisms of collateral sensitivity are required.