Mechanism of eravacycline resistance in Acinetobacter baumannii mediated by a deletion mutation in the sensor kinase adeS, leading to elevated expression of the efflux pump AdeABC.

ABSTRACT

Acinetobacter baumannii is an important pathogen and presents a major burden in healthcare as strains frequently cause hospital associated opportunistic infections with high mortality rates. Due to increasing numbers of drug resistant A. baumannii strains, newly developed antibiotics are being used to treat infections caused by such strains. One novel synthetic antibiotic of the tetracycline class with activity against A. baumannii is eravacycline. To investigate possible mechanisms of eravacycline resistance, we performed an in vitro evolution experiment to select for an eravacycline resistant strain, with the clinical isolate MDR-ZJ06 as parental strain. We obtained a strain designated MDR-ZJ06-E6 that was able to grow in 64-fold MIC. Genomic mutations were identified by whole genome sequencing, where we found a deletion mutation in the gene adeS. Using complementation experiments, including growth rate determination and antibiotics susceptibility testing, we could confirm that this mutation was responsible for eravacycline resistance of strain MDR-ZJ06-E6. As a mechanism of resistance, we identified a significant overexpression of the efflux pump AdeABC which seems to be regulated by the mutation in adeS in A. baumannii.