Abstract
In this study, we developed tigecycline resistance in Klebsiella pneumoniae ST23 strains in vitro and investigated the change in virulence associated with hypermucoviscosity. In vitro-induced tigecycline-resistant (TGC-IR) K. pneumoniae mutants were obtained from three tigecycline-susceptible (TGC-S) strains, belonging to ST23 and serotype K1, by culturing in media with tigecycline in a stepwise manner. An antimicrobial susceptibility test, string test, mucoviscosity assay, and capsular polysaccharide (CPS) quantification were performed. Biofilm formation and serum resistance were evaluated, and survival rates of bacterial strains in fruit flies and macrophages were measured. Alterations of rpsJ, ramR, soxR, acrR, and marR genes were investigated and the expression levels of ramA and efflux pump genes were evaluated. The hypermucoviscosity phenotype was dramatically decreased in the TGC-IR mutants. Reduced CPS production in TGC-IR mutants was also identified. Increased resistance to most other antimicrobial agents was found in TGC-IR mutants. In addition, the TGC-IR mutants exhibited reduced biofilm formation, low serum resistance, and decreased survival rates within fruit flies and macrophages. Our study shows that development of tigecycline resistance in hypervirulent K. pneumoniae strains result in defects in virulence associated with hypermucoviscosity.
Highlights
Klebsiella pneumoniae is a Gram-negative bacillus that is responsible for both community-acquired and nosocomial infections including pneumonia, urinary tract infections, bacteremia, and liver abscesses [1]
Sequence type 23 (ST23) is the most commonly described among hypermucoviscous K. pneumoniae isolates and is strongly correlated with capsular serotype K1 and liver abscess [1,6,7]
We investigated the association between tigecycline resistance and HV in hypervirulent K. pneumoniae (hvKP) isolates belonging to sequence type 23 (ST23)
Summary
Klebsiella pneumoniae is a Gram-negative bacillus that is responsible for both community-acquired and nosocomial infections including pneumonia, urinary tract infections, bacteremia, and liver abscesses [1]. An increase in carbapenem resistance in K. pneumoniae worldwide has limited the available treatment options for the bacterium. Tigecycline is a last-resort antibiotic reserved for treatment in carbapenem-resistant K. pneumoniae infection [8]. Tigecycline resistance means that options for the treatment of carbapenem-resistant K. pneumoniae infections are virtually eliminated. In K. pneumoniae, resistance to tigecycline is mainly attributed to overproduction of efflux pumps (AcrAB, OqxA, KpgAB) [11] and to mutations in efflux pump regulator genes (ramA, soxR, marR, acrR) [12]. Mutations in ramR, which encodes a transcriptional repressor belonging to the TetR family, are responsible for tigecycline resistance by leading to the overexpression of ramA. Mutations in rpsJ, the gene that encodes the ribosomal S10 protein, could confer reduced susceptibility to tigecycline in K. pneumoniae [13]
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