Development of Resistance to Eravacycline by Klebsiella pneumoniae and Collateral Sensitivity-Guided Design of Combination Therapies.

The evolution of bacterial antibiotic resistance is exhausting the list of currently used antibiotics and endangers those in the pipeline. The combination of antibiotics is a promising strategy that may suppress resistance development and/or achieve synergistic therapeutic effects. Eravacycline is a newly approved antibiotic that is effective against a variety of multidrug-resistant (MDR) pathogens. However, the evolution of resistance to eravacycline and strategies to suppress the evolution remain unexplored. Here, we demonstrated that a carbapenem-resistant Klebsiella pneumoniae clinical isolate quickly developed resistance to eravacycline, which is mainly caused by mutations in the gene encoding the Lon protease. The evolved resistant mutants display collateral sensitivities to ß-lactam/ß-lactamase inhibitor (BLBLI) combinations aztreonam/avibactam and ceftazidime-avibactam. Proteomic analysis revealed upregulation of the multidrug efflux system AcrA-AcrB-TolC and porin proteins OmpA and OmpU, which contributed to the increased resistance to eravacycline and susceptibility to BLBLIs, respectively. The combination of eravacycline with aztreonam/avibactam or ceftazidime-avibactam suppresses resistance development. We further demonstrated that eravacycline-resistant mutants evolved from an NDM-1-containing K. pneumoniae strain display collateral sensitivity to aztreonam/avibactam, and the combination of eravacycline with aztreonam/avibactam suppresses resistance development. In addition, the combination of eravacycline with aztreonam/avibactam or ceftazidime-avibactam displayed synergistic therapeutic effects in a murine cutaneous abscess model. Overall, our results revealed mechanisms of resistance to eravacycline and collateral sensitivities to BLBLIs and provided promising antibiotic combinations in the treatment of multidrug-resistant K. pneumoniae infections. IMPORTANCE The increasing bacterial antibiotic resistance is a serious threat to global public health, which demands novel antimicrobial medicines and treatment strategies. Eravacycline is a newly approved antibiotic that belongs to the tetracycline antibiotics. Here, we found that a multidrug-resistant Klebsiella pneumoniae clinical isolate rapidly developed resistance to eravacycline and the evolved resistant mutants displayed collateral sensitivity to antibiotics aztreonam/avibactam and ceftazidime-avibactam. We demonstrated that the combination of eravacycline with aztreonam/avibactam or ceftazidime-avibactam repressed resistance development and improved the treatment efficacies. We also elucidated the mechanisms that contribute to the increased resistance to eravacycline and susceptibility to aztreonam/avibactam and ceftazidime-avibactam. This work demonstrated the mechanisms of antibiotic resistance and collateral sensitivity and provided a new therapeutically option for effective antibiotic combinations.

Adsorption of uranium (VI) from aqueous solution using a novel graphene oxide-activated carbon felt composite.

Graphene oxide(GO)-activated carbon felt(ACF)(GO-ACF) composite was prepared by an electrophoretic deposition and subsequent thermal annealing. The structures of GO and GO-ACF were characterized by FT-IR, Raman spectra and XPS. The adsorption capacities for U(VI) from aqueous solution of ACF and GO-ACF were compared. The essential factors affected U(VI) adsorption such as initial pH, contact time and temperature were investigated. The adsorption is highly dependent on the solution pH. In addition, the adsorption isotherm and thermodynamics were investigated. The adsorptions of U(VI) from aqueous solution on GO-ACF were fitted to the Langmuir and, Freundlich adsorption isotherms. The adsorption of U(VI) could be well-described by Langmuir. The adsorption of U(VI) on ACF is remarkably improved by GO covalently bonding with ACF. The maximum sorption capacity of GO-ACF for U(VI) was evaluated to be 298 mg/g at pH 5.5, much higher than that of ACF (173 mg/g), suggesting the carboxyl functional groups of GO-ACF playing important roles in the sorption. Thermodynamic parameters further show that the sorption is an endothermic and spontaneous process. GO-ACF is a powerful promising sorbent for the efficient removal of U(VI) from aqueous solutions.