Bacteriophage Effectively Rescues Pneumonia Caused by Prevalent Multidrug-Resistant
            <i>Klebsiella pneumoniae</i>
            in the Early Stage

Gan, Lu; Fu, Hanyu; Tian, Ziyan; Cui, Jinghua; Yan, Chao; Xue, Guanhua; Fan, Zheng; Du, Bing; Feng, Jian; Zhao, Huiru; Feng, Yinchang; Xu, Ziying; Fu, Tongtong; Cui, Xiaohu; Zhang, Rui; Du, Shuheng; Liu, Shiyu; Zhou, Yao; Zhang, Qun; Cao, Ling; Yuan, Jing

doi:10.1128/spectrum.02358-22

Cited by 19 publications

(10 citation statements)

References 43 publications

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“…On the 7th-day post-challenge, TNF-α levels in the phage-treated infected groups were significantly lower than in the un-treat group but still high than in the synergism group. The involvement of the immune response in the success of respiratory phage therapy was previously demonstrated and modeled [ 55 ]. Another study showed phages targeting host strains regulate pro-inflammatory and anti-inflammatory cytokines in mice [ 56 ].…”

Section: Discussionmentioning

confidence: 99%

Characterization of novel bacteriophage PSKP16 and its therapeutic potential against β-lactamase and biofilm producer strain of K2-Hypervirulent Klebsiella pneumoniae pneumonia infection in mice model

Rahimi,

Bakht,

Javadi

et al. 2023

BMC Microbiol

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Background Severe infections caused by β- lactamase producers, hypervirulent Klebsiella pneumoniae (BhvKp) with K2 serotype, highlight emergency need for new therapeutic strategies against this pathogen. We aimed to assess the efficacy of a novel phage, PSKP16, in the treating of pneumonia induced by BhvKp in mice models. Method Genome sequences of PSKP16 were analyzed, and associated information can be found in NCBI. We applied treatment in two ways: by using mice for immediate and delayed treatments. Moreover, acute pneumonia obtained by BhvKp with intranasal method, was characterized in terms of histopathology of pulmonary lesions, biomarkers of inflammation level, leukocytes cells infiltration extent in mice, and was assessed treatment of them with PSKP16 multiplicity of infection (MOI: 10), either individually or in combination with gentamicin. Assessment of the ability of PSKP16 to inhibit BhvKp biofilm was studied. Results PSKP16 was associated with the Drexlerviridae family, and had a genome size of 46,712 bp, and 67 predicted ORFs. Herein, prompt phage administration’s efficacy to decrease bacterial load and improve the survival rate in pneumonia models was faster than the synergism model with delay, but both almost displayed similar endpoints. The distribution of BhvKp strains in the lung was consistent with the histopathological findings, simultaneous inflammation, and level of serum tumor necrosis factor-α (TNF α). The phage treatment presented a lack of severe lesions and alveolar edema, reduction of inflammatory cell infiltration, which not only was it not associated with an over-inflammation but also provided a faster correction of blood cell count abnormalities compared to gentamicin. Phage with a high concentration in in vitro model effectively eliminated biofilms. Conclusion It is essential to raise clinical awareness and management of BhvKp infections, signaled as the next superbug in waiting. The results of our study underscore the importance of PSKP16 as a phage with promising therapeutic potential in treating BhvKp-induced pneumonia.

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Section: Discussionmentioning

confidence: 99%

Characterization of novel bacteriophage PSKP16 and its therapeutic potential against β-lactamase and biofilm producer strain of K2-Hypervirulent Klebsiella pneumoniae pneumonia infection in mice model

Rahimi,

Bakht,

Javadi

et al. 2023

BMC Microbiol

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“…The minimum lethal dose (MLD)was determined, and the animal model was constructed according to previous reports [ 21 , 22 ]. Briefly, the mice were randomly allocated into four groups: (1) the K. aerogenes group (n = 25), which received an intratracheal/endobronchial instillation of 2 × 10 7 CFU K. aerogenes (2 × MLD) and intranasal delivery of normal saline; (2) the K. aerogenes + pK4-26 group (n = 25), which received an intratracheal/endobronchial instillation of 2 × 10 7 CFU K. aerogenes and intranasal delivery of 2 × 10 9 PFU pK4-26; (3) the pK4-26 group (n = 25), which received an intratracheal/endobronchial instillation of normal saline and intranasal delivery of 2 × 10 9 PFU pK4-26; and (4) the paired group (n = 25), which received an intratracheal/endobronchial instillation of normal saline and intranasal delivery of normal saline.…”

Section: Methodsmentioning

confidence: 99%

A novel phage carrying capsule depolymerase effectively relieves pneumonia caused by multidrug-resistant Klebsiella aerogenes

Cui,

Du,

Feng

et al. 2023

J Biomed Sci

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Background Klebsiella aerogenes can cause ventilator-associated pneumonia by forming biofilms, and it is frequently associated with multidrug resistance. Phages are good antibiotic alternatives with unique advantages. There has been a lack of phage therapeutic explorations, kinetic studies, and interaction mechanism research targeting K. aerogenes. Methods Plaque assay, transmission electron microscopy and whole-genome sequencing were used to determine the biology, morphology, and genomic characteristics of the phage. A mouse pneumonia model was constructed by intratracheal/endobronchial delivery of K. aerogenes to assess the therapeutic effect of phage in vivo. Bioinformatics analysis and a prokaryotic protein expression system were used to predict and identify a novel capsule depolymerase. Confocal laser scanning microscopy, Galleria mellonella larvae infection models and other experiments were performed to clarify the function of the capsule depolymerase. Results A novel lytic phage (pK4-26) was isolated from hospital sewage. It was typical of the Podoviridae family and exhibited serotype specificity, high lytic activity, and high environmental adaptability. The whole genome is 40,234 bp in length and contains 49 coding domain sequences. Genomic data show that the phage does not carry antibiotic resistance, virulence, or lysogenic genes. The phage effectively lysed K. aerogenes in vivo, reducing mortality and alleviating pneumonia without promoting obvious side effects. A novel phage-derived depolymerase was predicted and proven to be able to digest the capsule, remove biofilms, reduce bacterial virulence, and sensitize the bacteria to serum killing. Conclusions The phage pK4-26 is a good antibiotic alternative and can effectively relieve pneumonia caused by multidrug-resistant K. aerogenes. It carries a depolymerase that removes biofilms, reduces virulence, and improves intrinsic immune sensitivity.

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“…In a mouse model of infection, phage treatment improved survival; 53 it was demonstrated that phage pKp11 and pKp383 lysed 51 strains of multidrug-resistant K. pneumoniae (including strains ST11 and ST383), providing an effective treatment for the early stages of pneumonia in a mouse model of infection without significant side effects. 54 Scientists at the National Institutes of Health (NIH) successfully treated mice infected with multidrug-resistant K. pneumoniae ST258 using two different phage viruses, alone and in combination. These findings are encouraging and show successful therapeutic effects in animal models.…”

Section: Phagesmentioning

confidence: 99%

Mechanisms of Antibiotic Resistance and Developments in Therapeutic Strategies to Combat Klebsiella pneumoniae Infection

Li,

Kumar,

Zhang

2024

IDR

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Infections with drug-resistant bacteria have become one of the greatest public health challenges, and K. pneumoniae is among the top six drug-resistant bacteria. K. pneumoniae often causes nosocomial infections, leading to illnesses such as pneumonia, liver abscesses, soft tissue infections, urinary tract infections, bacteremia, and in some cases death. As the pathogen continues to evolve and its multidrug resistance increases, K. pneumoniae poses a direct threat to humans. Drug resistance in K. pneumoniae may occur due to the formation of biofilms, efflux pumps, and the production of β-lactamases. In many cases, resistance is further enhanced by enzymatic modification and loss of porins. Drug resistance to K. pneumoniae has led to a decline in the effectiveness of conventional therapies against this pathogen. Therefore, there is an urgent need to accelerate the development of new antibiotics and explore new therapeutic approaches such as antimicrobial peptides, phages, traditional Chinese medicine, immunotherapy, Antimicrobial nanoparticle technology, antisense oligonucleotides and gene editing technologies. In this review, we discuss the mechanisms of drug resistance in K. pneumoniae and compare several new potential therapeutic strategies to overcome drug resistance in the treatment of K. pneumoniae infections.

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Bacteriophage Effectively Rescues Pneumonia Caused by Prevalent Multidrug-Resistant Klebsiella pneumoniae in the Early Stage

Abstract: K. pneumoniae is recognized as the most common pathogen of hospital- and community-acquired pneumonia across the world. The strains of ST11 and ST383 are frequently reported in patients with pneumonia.

Cited by 19 publications

References 43 publications

Characterization of novel bacteriophage PSKP16 and its therapeutic potential against β-lactamase and biofilm producer strain of K2-Hypervirulent Klebsiella pneumoniae pneumonia infection in mice model

Characterization of novel bacteriophage PSKP16 and its therapeutic potential against β-lactamase and biofilm producer strain of K2-Hypervirulent Klebsiella pneumoniae pneumonia infection in mice model

A novel phage carrying capsule depolymerase effectively relieves pneumonia caused by multidrug-resistant Klebsiella aerogenes

Mechanisms of Antibiotic Resistance and Developments in Therapeutic Strategies to Combat Klebsiella pneumoniae Infection

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