Abstract
Background Klebsiella pneumoniae is a Gram-negative, non-motile, facultative anaerobe belonging to the Enterobacteriaceae family of the γ-Proteobacteria class in the phylum Proteobacteria. Multidrug resistant K. pneumoniae have caused major therapeutic problems worldwide due to emergence of extended-spectrum β-lactamase producing strains. Two-component systems serve as a basic stimulus-response coupling mechanism to allow organisms to sense and respond to changes in many different environmental conditions including antibiotic stress.Principal FindingsIn the present study, we investigated the role of an uncharacterized cpxAR operon in bacterial physiology and antimicrobial resistance by generating isogenic mutant (ΔcpxAR) deficient in the CpxA/CpxR component derived from the hyper mucoidal K1 strain K. pneumoniae NTUH-K2044. The behaviour of ΔcpxAR was determined under hostile conditions, reproducing stresses encountered in the gastrointestinal environment and deletion resulted in higher sensitivity to bile, osmotic and acid stresses. The ΔcpxAR was more susceptible to β-lactams and chloramphenicol than the wild-type strain, and complementation restored the altered phenotypes. The relative change in expression of acrB, acrD, eefB efflux genes were decreased in cpxAR mutant as evidenced by qRT-PCR. Comparison of outer membrane protein profiles indicated a conspicuous difference in the knock out background. Gel shift assays demonstrated direct binding of CpxRKP to promoter region of ompC KP in a concentration dependent manner.Conclusions and SignificanceThe Cpx envelope stress response system is known to be activated by alterations in pH, membrane composition and misfolded proteins, and this systematic investigation reveals its direct involvement in conferring antimicrobial resistance against clinically significant antibiotics for the very first time. Overall results displayed in this report reflect the pleiotropic role of the CpxAR signaling system and diversity of the antibiotic resistome in hyper virulent K1 serotype K. pneumoniae NTUH-K2044.
Highlights
Bacteria can encounter numerous environments in which chemical and physical factors such as osmotic pressure, temperature, pH and carbon source availability can change considerably and unpredictably [1]
The Cpx envelope stress response system is known to be activated by alterations in pH, membrane composition and misfolded proteins, and this systematic investigation reveals its direct involvement in conferring antimicrobial resistance against clinically significant antibiotics for the very first time
Overall results displayed in this report reflect the pleiotropic role of the CpxAR signaling system and diversity of the antibiotic resistome in hyper virulent K1 serotype K. pneumoniae NTUH-K2044
Summary
Bacteria can encounter numerous environments in which chemical and physical factors such as osmotic pressure, temperature, pH and carbon source availability can change considerably and unpredictably [1]. To adapt to changing conditions, bacteria possess an array of mechanisms which sense external factors and respond central to this are the two component systems (TCS) [2]. TCS are signal transduction devices found in all domains of life, and they are especially widespread in bacteria. These systems regulate diverse responses, including nutrient acquisition, energy metabolism, adapting to environmental cues, complex developmental pathways, and host-pathogen interactions. The transmembrane sensor component harbors at least two domains: an input domain that senses the environmental stimulus and a cytoplasmic transmitter with kinase activity that alters the external stimulus into an adaptive signal by autophosphorylation at a conserved histidine residue. Twocomponent systems serve as a basic stimulus-response coupling mechanism to allow organisms to sense and respond to changes in many different environmental conditions including antibiotic stress
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