Phage Selective Pressure Reduces Virulence of Hypervirulent Klebsiella pneumoniae Through Mutation of the wzc Gene

Abstract

Hypervirulent Klebsiella pneumoniae (hvKp), one of the major community-acquired pathogens, can cause invasive infections such as liver abscess. In recent years, bacteriophages have been used in the treatment of K. pneumoniae, but the characteristics of the phage-resistant bacteria produced in the process of phage therapy need to be evaluated. In this study, two Podoviridae phages, hvKpP1 and hvKpP2, were isolated and characterized. In vitro and in vivo experiments demonstrated that the virulence of the resistant bacteria was significantly reduced compared with that of the wild type. Comparative genomic analysis of monoclonal sequencing showed that nucleotide deletion mutations of wzc and wcaJ genes led to phage resistance, and the electron microscopy and mucoviscosity results showed that mutations led to the loss of the capsule. Meanwhile, animal assay indicated that loss of capsule reduced the virulence of hvKp. These findings contribute to a better understanding of bacteriophage therapy, which not only can kill bacteria directly but also can reduce the virulence of bacteria by phage screening.

Phage-antibiotic combination is a superior treatment against Acinetobacter baumannii in a preclinical study

“…However, we hypothesise that similar results could be obtained with other phages that target A. baumannii ’s capsule, thus inducing capsule loss upon emergence of phage-resistance. It could even be possible for similar phenomena to emerge with other capsulated pathogens, as suggested by preliminary observations in Klebsiella pneumoniae 65 and Pseudomonas aeruginosa . 66 A final caveat regarding phage øFG02 is that, despite multiple attempts, 33 its genome remains unsequenced.…”

Fitness Trade-Offs in Phage Cocktail-Resistant Salmonella enterica Serovar Enteritidis Results in Increased Antibiotic Susceptibility and Reduced Virulence

“…In phage-host interactions, modification/masking of bacterial surface receptors to evolve constitutive defenses against phages is often associated with fitness costs ( 20 , 34 – 37 ). To our knowledge, the type of fitness cost is mainly determined by the receptor type of the host, such as OMPs or LPSs.…”

Evolution of Virulence, Fitness, and Carbapenem Resistance Transmission in ST23 Hypervirulent Klebsiella pneumoniae with the Capsular Polysaccharide Synthesis Gene wcaJ Inserted via Insertion Sequence Elements

“…A recent study reported that mutations in genes essential for capsule biosynthesis in Acinetobacter baumannii confer resistance to phage adsorption through capsule loss ( 28 ). Similarly, the wcaJ gene is related to phage sensitivity ( 29 ), and its absence might protect isolates, particularly CR-hvKP, from lytic phage predation in vitro and in vivo ( 24 , 30 ), thus enhancing their viability.…”