Abstract
Bacterial heteroresistance has been identified in several combinations of bacteria and antibiotics, and it complicated the therapeutic strategies. Tigecycline is being used as one of the optimal options for the treatment of infections caused by multidrug-resistant Salmonella. This study investigated whether heterorresistance to tigecycline exists in a Salmonella enterica serovar Typhimurium strain harboring the oqxAB-bearing IncHI2 plasmid pHXY0908. MIC and population analyses were performed to evaluate population-wide susceptibility to tigecycline. The effects of efflux pumps on MIC levels were assessed using the efflux pump inhibitor Phe-Arg-β-naphthylamide, measuring intracellular tigecycline accumulation as well as mRNA levels of regulatory and efflux pump genes. DNA sequencing of regulatory regions were performed and plasmid curing from a resistant strain provided an appropriate control. Results showed that MICs of a parental strain with and without pHXY0908 as well as a plasmid-cured strain 14028/Δp52 were 0.5, 1, and 1 μg/mL, respectively. Population analysis profiling (PAP) illustrated that only the pHXY0908-containg strain was heteroresistant to tigecycline. A fraction of colonies exhibited stable profiles with 4- to 8-fold increases in MIC. The frequencies of emergence of these isolates were higher in the plasmid-containing strain pHXY0908 than either the parental or the 14028/Δp52 strain. Phe-Arg-β-naphthylamide addition restored tigecycline susceptibility of these isolates and intracellular tigecycline accumulation was reduced. Heteroresistant isolates of the strain containing pHXY0908 also had elevated expression of acrB, ramA, and oqxB. DNA sequencing identified numerous mutations in RamR that have been shown to lead to ramA overexpression. In conclusions, heteroresistance to tigecycline in Salmonella enterica serovar Typhimurium was manifested in a plasmid-bearing strain. Our results suggest that this phenotype was associated with overexpression of the AcrAB-TolC and OqxAB efflux pumps.
Highlights
Salmonella enterica serovar Typhimurium is an important zoonotic pathogen that leads to various infections in humans and the proliferation of multidrug-resistant isolates, especially those extended-spectrum β-lactamase-producing and fluoroquinolone-resistant strains are of major concerns (Fàbrega et al, 2008)
As efflux pumps are implicated in tigecycline resistance in Salmonella, we examined whether efflux pumps were associated with tigecycline heteroresistance
This study illustrates that heteroresistance to tigecycline in S
Summary
Salmonella enterica serovar Typhimurium is an important zoonotic pathogen that leads to various infections in humans and the proliferation of multidrug-resistant isolates, especially those extended-spectrum β-lactamase-producing and fluoroquinolone-resistant strains are of major concerns (Fàbrega et al, 2008). Carbapenems and colistin were therapeutic options for treatment of severe infections caused by multidrug-resistant bacteria such as the Typhimurium serovar (Taneja and Kaur, 2016). Tigecycline represents a new class of antibiotic agents, the glycylcyclines. This compound exhibits an extraordinarily broad-spectrum of activity against pathogens, including difficult-to-treat pathogens such as carbapenemase- or extended-spectrum β-lactamases-producing Gram-negative bacteria (Stein and Babinchak, 2013). Tigecycline is readily transported into the cell and achieves high intracellular concentrations (Ong et al, 2005). This is a key factor when considering treatment of invasive infections caused by multidrug-resistant Salmonella (Tang et al, 2016)
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