Zinc Finger Nuclease: A New Approach to Overcome Beta-Lactam Antibiotic Resistance

Dastjerdeh, Mansoureh Shahbazi; Kouhpayeh, Shirin; Sabzehei, Faezeh; Khanahmad, Hossein; Salehi, Masoud; Mohammadi, Zahra; Shariati, Laleh; Hejazi, Zahra; Rabiei, Parisa; Manian, Mostafa

doi:10.5812/jjm.29384

Cited by 19 publications

(19 citation statements)

References 41 publications

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“…For these reasons, among others, it is crucial that we begin to develop new treatments to combat bacterial infection. Researchers have already begun investigating potential new antimicrobial strategies (22), such as the use of antimicrobial peptides (23, 24), phage therapy (25, 26), and gene-editing enzymes (27, 28). Here, we report another promising novel approach: the use of predatory bacteria to control Gram-negative human pathogens.…”

Section: Discussionmentioning

confidence: 99%

Predatory Bacteria Attenuate Klebsiella pneumoniae Burden in Rat Lungs

Shatzkes

Singleton

Tang

et al. 2016

mBio

101

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Bdellovibrio bacteriovorus and Micavibrio aeruginosavorus are predatory bacteria that naturally—and obligately—prey on other Gram-negative bacteria, and their use has been proposed as a potential new approach to control microbial infection. The ability of predatory bacteria to prey on Gram-negative human pathogens in vitro is well documented; however, the in vivo safety and efficacy of predatory bacteria have yet to be fully assessed. In this study, we examined whether predatory bacteria can reduce bacterial burden in the lungs in an in vivo mammalian system. Initial safety studies were performed by intranasal inoculation of rats with predatory bacteria. No adverse effects or lung pathology were observed in rats exposed to high concentrations of predatory bacteria at up to 10 days postinoculation. Enzyme-linked immunosorbent assay (ELISA) of the immune response revealed a slight increase in inflammatory cytokine levels at 1 h postinoculation that was not sustained by 48 h. Additionally, dissemination experiments showed that predators were efficiently cleared from the host by 10 days postinoculation. To measure the ability of predatory bacteria to reduce microbial burden in vivo, we introduced sublethal concentrations of Klebsiella pneumoniae into the lungs of rats via intranasal inoculation and followed with multiple doses of predatory bacteria over 24 h. Predatory bacteria were able to reduce K. pneumoniae bacterial burden, on average, by more than 3.0 log10 in the lungs of most rats as measured by CFU plating. The work presented here provides further support for the idea of developing predatory bacteria as a novel biocontrol agent.

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Section: Discussionmentioning

confidence: 99%

Predatory Bacteria Attenuate Klebsiella pneumoniae Burden in Rat Lungs

Shatzkes

Singleton

Tang

et al. 2016

mBio

101

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“…A previous study has suggested that zinc finger nuclease may be a potential agent to overcome β-lactam antibiotic resistance (23). Antibiotic resistance of Klebsiella pneumoniae has challenged the therapeutic efficacy for patients with pneumonia (35).…”

Section: Discussionmentioning

confidence: 99%

“…A previous study indicates that zinc finger nuclease technology is able to target and disrupt gene-encoded β-lactamase, which prevents horizontal gene transfer-mediated evolution of antibiotic resistant bacteria and antibiotic resistance genes (23). Therefore, we analyzed the function of zinc finger nuclease in Klebsiella pneumoniae.…”

Section: Efficacy Of Zinc Finger Nuclease For Growth Of Klebsiella Pnmentioning

confidence: 99%

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Klebsiella pneumoniae presents antimicrobial drug resistance for β‑lactam through the ESBL/PBP signaling pathway

et al. 2020

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Overuse and misuse of antibiotics leads to antibiotic resistance which has become a significant public health concern. Klebsiella pneumoniae is the most common pathogenic bacteria underlying nosocomial infections due to the expression of virulence factors and occurrence of antibiotic resistance. Evidence indicates that β-lactamase is involved in the antibiotic resistance of Klebsiella pneumoniae to β-lactam antibiotics. The aim of the present study was to investigate the association between the molecular biological mechanisms of antibiotic resistance of Klebsiella pneumoniae and extended-spectrum β-lactamase (ESBL). In order to assess temporal trends in prevalence and antimicrobial susceptibility, Klebsiella pneumoniae bacteria were isolated and the ESBL expression level was analyzed. Susceptibility tests were performed using automated systems. The β-lactam-resistance in Klebsiella pneumoniae was assessed by the β-lactam agar screen plate and respective MIC values were evaluated using E-test strips. The confirmatory disk diffusion methods were applied for phenotypic identification of the ESBL production of Klebsiella pneumoniae. The results showed that Klebsiella pneumoniae bacteria exhibited higher ESBL production after treatment with β-lactam compared to the control. The ESBL gene expression was upregulated in Klebsiella pneumoniae after treatment with β-lactam. Results identified that penicillin-binding proteins (PBPs) were associated with the growth and resistance to β-lactams. Zinc finger nuclease markedly inhibited the antibiotic resistance of Klebsiella pneumoniae to β-lactam. PBP knockdown abolished the inhibitory effects of zinc finger nuclease on the growth of Klebsiella pneumoniae induced by β-lactam antibiotic treatment. In conclusion, these results suggest that the resistance of Klebsiella pneumoniae bacteria to antimicrobial drugs is through the ESBL signaling pathway, which indicates that ESBL may be a potential target for abolishing resistance to β-lactam.

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“…This might be the possible explanation of severe lung injury in COVID -19 patients. Moreover, TRPM2 ability to response to oxidative stress made it a promising target for development of new small molecule and therapeutic approach suchas aptamer(31) and gene editing tools(32,33)(Fig 1).…”

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confidence: 99%

The Molecular Story of COVID-19; NAD<sup>+</sup><sup> </sup>Depletion Addresses All Questions in this Infection

Kouhpayeh¹,

Shariati²,

Boshtam³

et al. 2020

Preprint

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The emerging new Coronaviridae member, nCoV 19, outbreak announced a pandemic by WHO with an increased morbidity and mortality rate worldwide. nCoV 19 known as the third highly pathogen coronavirus in the human population after the severe acute respiratory syndrome coronavirus (SARS-CoV) and the Middle East respiratory syndrome coronavirus (MERS-CoV), the nCoV 19. The renin-angiotensin (RAS) signaling pathway, oxidative stress and cell death, cytokines storm and endothelial dysfunction are four major pathways involved in the pathogenesis of nCoV 19. Acute respiratory distress syndrome (ARDS) generally develops with a massive oxidative/nitrosative stress following virus entry and RAS activation. The DNA damage subsequent to oxidative burst activates poly-ADP ribose polymerase-1 (PARP-1), viral macrodomain (NSP3) poly (ADP-ribose) glycohydrolase (PARG) and transient receptor potential channel, melastatin 2 (TRPM2) in a sequential manner ultimately leading to apoptosis and necrosis due to NAD and ATP depletion. Regarding the molecular mechanisms involved in nCoV 19 pathogenesis, angiotensin II receptor blockers and/or PARP, PARG and TRPM2 blockers could be engaged as therapeutic candidates for inhibition of RAS and quenching oxidative stress, respectively. In this review, the molecular aspects of nCoV 19 pathogenesis would be studied precisely and possible therapeutic targets would be proposed. It is recommended to evaluate the proposed drugs and supplements via registered clinical trials along with conventional guideline-based multi-drug regimen.

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Zinc Finger Nuclease: A New Approach to Overcome Beta-Lactam Antibiotic Resistance

Cited by 19 publications

References 41 publications

Predatory Bacteria Attenuate Klebsiella pneumoniae Burden in Rat Lungs

Predatory Bacteria Attenuate Klebsiella pneumoniae Burden in Rat Lungs

Klebsiella pneumoniae presents antimicrobial drug resistance for β‑lactam through the ESBL/PBP signaling pathway

The Molecular Story of COVID-19; NAD<sup>+</sup><sup> </sup>Depletion Addresses All Questions in this Infection

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