Abstract
Carbapenem-resistant Enterobacteriaceae (CRE) organisms have emerged to become a major global public health threat among antimicrobial resistant bacterial human pathogens. Little is known about how CREs emerge. One characteristic phenotype of CREs is heteroresistance, which is clinically associated with treatment failure in patients given a carbapenem. Through in vitro whole-transcriptome analysis we tracked gene expression over time in two different strains (BR7, BR21) of heteroresistant KPC-producing Klebsiella pneumoniae, first exposed to a bactericidal concentration of imipenem followed by growth in drug-free medium. In both strains, the immediate response was dominated by a shift in expression of genes involved in glycolysis toward those involved in catabolic pathways. This response was followed by global dampening of transcriptional changes involving protein translation, folding and transport, and decreased expression of genes encoding critical junctures of lipopolysaccharide biosynthesis. The emerged high-level carbapenem-resistant BR21 subpopulation had a prophage (IS1) disrupting ompK36 associated with irreversible OmpK36 porin loss. On the other hand, OmpK36 loss in BR7 was reversible. The acquisition of high-level carbapenem resistance by the two heteroresistant strains was associated with distinct and shared stepwise transcriptional programs. Carbapenem heteroresistance may emerge from the most adaptive subpopulation among a population of cells undergoing a complex set of stress-adaptive responses.
Highlights
In 2013, the Centers for Disease Control and Prevention (CDC) designated carbapenem-resistant Enterobacteriaceae (CRE) as “urgent threat” pathogens [1]
The blaKPC gene that encodes the enzyme is carried on several types of plasmids that are readily transmitted to other Gram-negative species such as Escherichia coli, one of the most important causes of community-onset infections [4, 5]
We previously showed that exposure of carbapenemheteroresistant Klebsiella pneumoniae carbapenemase (KPC)-Kp strains to a bactericidal concentration of imipenem resulted in a reproducible, biphasic pattern of near-complete killing of the population, followed by recovery within 20 hours (h) [11]
Summary
In 2013, the Centers for Disease Control and Prevention (CDC) designated carbapenem-resistant Enterobacteriaceae (CRE) as “urgent threat” pathogens [1]. A Diverse Transcriptional Response Is Observed in Two Clonally Related Carbapenem-Heteroresistant Strains after Lethal Imipenem Exposure Followed by Growth in Drug-Free Medium. The plasmidmediated blaKPC gene was 100% identical in sequence in both strains and was not differentially expressed after imipenem exposure.
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