Abstract

The growing incidence of multidrug-resistant (MDR) bacteria is an emerging challenge in modern medicine. The utility of carbapenems, considered “last-line” agents in therapy of infections caused by MDR pathogens, is being diminished by the growing incidence of various resistance mechanisms. Enterobacter cloacae have lately begun to emerge as an important pathogen prone to exhibiting multiple drug resistance. We aimed to investigate the molecular basis of carbapenem-resistance in 44 E. cloacae clinical strains resistant to at least one carbapenem, and 21 susceptible strains. Molecular investigation of 65 E. cloacae clinical strains was based on quantitative polymerase chain reaction (qPCR) allowing for amplification of ampC, ompF, and ompC transcripts, and analysis of nucleotide sequences of alleles included in MLST scheme. Co-operation of three distinct carbapenem resistance mechanisms has been reported—production of OXA-48 (5%), AmpC overproduction (97.7%), and alterations in outer membrane (OM) transcriptome balance. Carbapenem-resistant E. cloacae were characterized by (1.) downregulation of ompF gene (53.4%), which encodes protein with extensive transmembrane channels, and (2.) the polarization of OM transcriptome-balance (79.1%), which was sloped toward ompC gene, encoding proteins recently reported to possess restrictive transmembrane channels. Subpopulations of carbapenem-susceptible strains showed relatively high degrees of sequence diversity without predominant types. ST-89 clearly dominates among carbapenem-resistant strains (88.6%) suggesting clonal spread of resistant strains. The growing prevalence of pathogens resistant to all currently available antimicrobial agents heralds the potential risk of a future “post-antibiotic era.” Great efforts need to be taken to explore the background of resistance to “last resort” antimicrobials.

Highlights

  • An enormous adaptive capacity of Gram-negative multidrug-resistant (MDR) bacteria enables them to accumulate many different mechanisms of resistance to various antimicrobial agents (Nikaido, 2009; Poole, 2011)

  • Pathogens were divided into two groups according to their susceptibility—44 E. cloacae clinical strains resistant to at least one carbapenem (CARB-R), and 21 susceptible strains (CARB-S)

  • We identified three distinct mechanisms that may contribute to the phenotype of resistance to carbapenems among tested E. cloacae subpopulations

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Summary

Introduction

An enormous adaptive capacity of Gram-negative multidrug-resistant (MDR) bacteria enables them to accumulate many different mechanisms of resistance to various antimicrobial agents (Nikaido, 2009; Poole, 2011). Carbapenem-Resistance in E. cloacae vital epidemiological problem is the emergence and spread of novel mechanisms of antimicrobial drug resistance, especially among subpopulations of pathogens persisting in hospital environments (Hawkey and Jones, 2009; Davin-Regli and Pagès, 2015). The prevalence of those highly resistant microorganisms contributes significantly to prolonged hospitalization and increased mortality (Cerceo et al, 2016; MacVane, 2017). The growing prevalence of pathogens resistant to most or even all currently available antimicrobial agents heralds the potential risk of a future “postantibiotic era” (Falagas and Bliziotis, 2007; Majewski et al, 2012). According to the estimates published in a UK report on the development of antimicrobial resistance, in 2050, infections caused by MDR microorganisms could become one of the most important causes of mortality worldwide (10 million deaths per year), surpassing even the mortality rate currently caused by cancer (8.2 million deaths per year) (Review on Antimicrobial Resistance, 2014)

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