Inactivation, or inhibition of AcrAB-TolC, increases resistance of carbapenemase-producing enterobacteriaceae to carbapenems

Research output: Contribution to journalArticle

Authors

External organisations

  • Antimicrobial Resistance and Healthcare Associated Infections (AMRHAI) Reference Unit, Public Health England, London, NW9 5EQ, United Kingdom

Abstract

Objectives: To study the contribution of the multi-drug resistance AcrAB-TolC efflux system and impact of the efflux inhibitor, PAβN, towards carbapenem resistance in carbapenemase-producing Enterobacteriaceae.
Methods: Klebsiella pneumoniae, Escherichia coli, Salmonella enterica serovar Typhimurium and their corresponding AcrAB-TolC mutants, each carrying carbapenemase carrying plasmids (pKpQIL-UK with blaKPC and pNDM-HK with blaNDM), were tested for their susceptibility to six β-lactam antibiotics according to the BSAC agar dilution method. MICs were also determined in the presence of efflux inhibitors. The susceptibility of ertapenem in the presence of 25 and 100 mg/L PAβN was also determined for 86 non-replicate clinical isolates of carbapenemase-producing Enterobacteriaceae with OXA-48-like (n=18), IMP (n=12), VIM (n=16), NDM (n=20) or KPC (n=20) enzymes. Outer membrane protein profiles were determined with SDS-PAGE.
Results: The carbapenemase producing AcrAB mutants of K. pneumoniae and E. coli, and TolC mutant of S. Typhimurium had elevated resistance to carbapenem antibiotics. In S. Typhimurium, the increase in carbapenem MIC correlated with the loss of OmpF. Sixty-two (72%) of the clinical isolates tested were also more resistant to ertapenem in the presence of PAβN. SDS-PAGE showed that the presence of PAβN affected outer membrane porin production, which was associated with the increased MIC values of ertapenem.
Conclusion: The decreased susceptibility to carbapenems of carbapenemase-producing Enterobacteriaceae in the absence of AcrAB or TolC and/or in the presence of an efflux inhibitor (e.g. PAβN) is likely due to the changes in porin expression (e.g. OmpF). Efflux inhibitors may not potentiate carbapenem activity, but rather could increase levels of resistance in carbapenemase-producing organisms.

Details

Original languageEnglish
JournalJournal of Antimicrobial Chemotherapy
Early online date5 Mar 2016
Publication statusE-pub ahead of print - 5 Mar 2016

Keywords

  • Efflux inhibitor, KPC, NDM, plasmid, PAβN, carbapenem