Abstract
Colistin is one of the few antibiotics that exhibit bactericidal effect on carbapenemase-producing Klebsiella pneumoniae strains. In recent years, however, colistin resistance is increasingly being reported among clinical carbapenem-resistant K. pneumoniae strains worldwide, posing serious challenge to treatment of infections caused by these organisms. In this study, we investigated one colistin-susceptible (YJH4) and one colistin-resistant (YJH15) K. pneumoniae strain, which were collected from a patient before and after colistin treatment, respectively. We characterized the effects of mgrB inactivation-induced colistin resistance on the physiological fitness and virulence in ST11 carbapenem-resistant K. pneumoniae both in vitro and in vivo. The colistin-resistant strain YJH15 was found to exhibit increased fitness and biofilm formation potential in vitro, and increased survival rate in the presence of normal human serum. Interestingly, YJH15 exhibited reduced virulence in the mouse infection model but enhanced virulence in Galleria mellonella infection model when compared to the colistin-susceptible parental strain YJH4. Infection with YJH15 was also found to result in lower expression level of inflammatory cytokine IL-1β in blood and significantly decreased bacterial loads in heart, liver, spleen, lung, kidney and blood. These results demonstrated that mgrB inactivation-induced colistin resistance has significant effects on multiple fitness and virulence-associated traits in K. pneumoniae.
Highlights
Klebsiella pneumoniae is one of the most common Gram-negative pathogens that cause nosocomial infections, among patients suffering from severe illnesses (Gomez-Simmonds and Uhlemann, 2017)
Using a polystyrene microtiter plate test approach, we examined the ability of K. pneumoniae strains to form biofilms
To determine the in vivo competition and systemic dissemination, ICR mice were inoculated with equal amounts of strain YJH4 and YJH15 (1*106 CFU mixed at a ratio of 1:1) by intravenous inoculation
Summary
Klebsiella pneumoniae is one of the most common Gram-negative pathogens that cause nosocomial infections, among patients suffering from severe illnesses (Gomez-Simmonds and Uhlemann, 2017). The incidence of carbapenem-resistant K. pneumoniae (CRKP) has significantly increased worldwide in recent decades (Munoz-Price et al, 2013; Hu et al, 2016). Polymyxins such as Phenotypic Changes Associated With Colistin Resistance colistin has become the only therapeutic option effective for treatment of infections caused by these carbapenemaseproducing organisms before the introduction of ceftazidimeavibactam, meropenem-vaborbactam and imipenem-relebactam in the clinical practice (Tumbarello et al, 2012). Structural alterations in two-component regulatory systems including PmrAB and PhoPQ, as well as mutations in the mgrB gene, are the main causes of colistin resistance in K. pneumoniae (Cannatelli et al, 2014). Colistin resistance is known to be associated with a significant biological cost in terms of overall physiological fitness and virulence in A. baumannii (Beceiro et al, 2014)
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