Abstract
Klebsiella pneumoniae is an opportunistic pathogen posing an urgent threat to global public health, and the capsule is necessary for K. pneumoniae infection and virulence. Phage-derived capsule depolymerases have shown great potential as antivirulence agents in treating carbapenem-resistant K. pneumoniae (CRKP) infections. However, the therapeutic potential of phages encoding depolymerases against CRKP remains poorly understood. In this study, we identified a long-tailed phage SRD2021 specific for mucoid CRKP with capsular K47 serotype, which is the predominant infectious K-type in Asia. Genome sequencing revealed that ΦSRD2021 belonged to the Drulisvirus genus and exhibited a capsular depolymerase domain in its tail fiber protein. A transposon-insertion library of host bacteria was constructed to identify the receptor for ΦSRD2021. We found that most phage-resistant mutants converted to a nonmucoid phenotype, including the mutant in wza gene essential for capsular polysaccharides export. Further knockout and complementation experiments confirmed that the Δwza mutant avoided adsorption by ΦSRD2021, indicating that the K47 capsular polysaccharide is the necessary receptor for phage infection. ΦSRD2021 lysed the bacteria mature biofilms and showed a therapeutic effect on the prevention and treatment of CRKP infection in the Galleria mellonella model. Furthermore, ΦSRD2021 also reduced the colonized CRKP in mouse intestines significantly. By recognizing the host capsule as a receptor, our results showed that ΦSRD2021 may be used as a potential antibacterial agent for K47 serotype K. pneumoniae infections.
Highlights
Klebsiella pneumoniae, a Gram-negative bacterium of the Enterobacteriaceae family, is a common agent of global community-acquired and healthcare-associated infections
Genes that code for the biosynthesis of K. pneumoniae capsule are located on a chromosomal operon, cps, harboring a series of genes such as wza, cpsB, and galF [2,3]
Clinical statistics suggest that capsule polysaccharides (CPS) produced by the infecting K. pneumoniae strain may be associated with the severity of infection, especially in communityacquired infections [1,4]
Summary
Klebsiella pneumoniae, a Gram-negative bacterium of the Enterobacteriaceae family, is a common agent of global community-acquired and healthcare-associated infections. Two major types of antibiotic resistance, the expression of extended-spectrum β-lactamases (ESBLs) and carbapenemases, have been commonly observed in K. pneumoniae [1]. Due to the lack of available effective treatments, ESBL-producing and carbapenem-resistant K. pneumoniae infections have significantly higher rates of morbidity and mortality than infections with nonresistant bacteria. K. pneumoniae capsule is a well-studied virulence factor, consisting of an elaborate layer of surface-associated polysaccharides, termed K antigens. It has been demonstrated that capsule polysaccharides (CPS) are critical for the resistance of K. pneumoniae to host defense, suppression of early inflammatory response, adherence, and biofilm formation [1]. Clinical statistics suggest that CPS produced by the infecting K. pneumoniae strain may be associated with the severity of infection, especially in communityacquired infections [1,4]. K1 and K2 serotype strains are generally more virulent than other serotypes; K47 and K64 are the most prevalent types in CRKP infections in Asia [5]
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