Antisense peptide nucleic acid inhibits the growth of KPC-producing Klebsiella pneumoniae strain

Silva, Késia Esther da; Ribeiro, Suzana Meira; Rossato, Luana; Santos, Caroline Paes dos; Preza, Sergio Espindola; Cardoso, Marlon Henrique; Franco, Octávio Luiz; Migliolo, Ludovico; Simionatto, Simone

doi:10.1016/j.resmic.2021.103837

Cited by 10 publications

(7 citation statements)

References 38 publications

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“…The conjugate was capable of inhibiting bacterial growth at 50 µM, with a concomitant reduction of the 16S gene amplification by ca. 97%, while 21% haemolysis was observed at this concentration 64 .…”

Section: Biopharmaceuticals; Antisense Peptide Nucleic Acid Antibioticsmentioning

confidence: 71%

Selected strategies to fight pathogenic bacteria

Plotniece

Sobolev

Supuran

et al. 2023

Journal of Enzyme Inhibition and Medicinal Chemistry

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Natural products and analogues are a source of antibacterial drug discovery. Considering drug resistance levels emerging for antibiotics, identification of bacterial metalloenzymes and the synthesis of selective inhibitors are interesting for antibacterial agent development. Peptide nucleic acids are attractive antisense and antigene agents representing a novel strategy to target pathogens due to their unique mechanism of action. Antisense inhibition and development of antisense peptide nucleic acids is a new approach to antibacterial agents. Due to the increased resistance of biofilms to antibiotics, alternative therapeutic options are necessary. To develop antimicrobial strategies, optimised in vitro and in vivo models are needed. In vivo models to study biofilm-related respiratory infections, device-related infections: ventilator-associated pneumonia, tissue-related infections: chronic infection models based on alginate or agar beads, methods to battle biofilm-related infections are discussed. Drug delivery in case of antibacterials often is a serious issue therefore this review includes overview of drug delivery nanosystems.

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Section: Biopharmaceuticals; Antisense Peptide Nucleic Acid Antibioticsmentioning

confidence: 71%

Selected strategies to fight pathogenic bacteria

Plotniece

Sobolev

Supuran

et al. 2023

Journal of Enzyme Inhibition and Medicinal Chemistry

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“…For phage therapy, this would presumably result in fewer mismatched host-phage combinations, hence rendering a better treatment ( Hyman, 2019 ). Although the current host range tests did not cover all 79 capsular types of K. pneumoniae ( Pan et al, 2015 ), both phages showed high specificity against K. pneumoniae including ESBL (+) K. pneumoniae strains isolated from clinical environment with high morbidity and mortality rates associated ( da Silva et al, 2021 ), indicating their potential in phage therapy ( Fayez et al, 2021 ; Supplementary Table S9 ). Furthermore, in the one-step growth curve experiment, KP1 and KP12 showed similar latent periods yet higher burst sizes than the previously reported Klebsiella phages ( Karumidze et al, 2013 ; Ciacci et al, 2018 ; Li et al, 2020 ).…”

Section: Discussionmentioning

confidence: 99%

Characterization of Klebsiella pneumoniae bacteriophages, KP1 and KP12, with deep learning-based structure prediction

et al. 2023

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Concerns over Klebsiella pneumoniae resistance to the last-line antibiotic treatment have prompted a reconsideration of bacteriophage therapy in public health. Biotechnological application of phages and their gene products as an alternative to antibiotics necessitates the understanding of their genomic context. This study sequenced, annotated, characterized, and compared two Klebsiella phages, KP1 and KP12. Physiological validations identified KP1 and KP12 as members of Myoviridae family. Both phages showed that their activities were stable in a wide range of pH and temperature. They exhibit a host specificity toward K. pneumoniae with a broad intraspecies host range. General features of genome size, coding density, percentage GC content, and phylogenetic analyses revealed that these bacteriophages are distantly related. Phage lytic proteins (endolysin, anti-/holin, spanin) identified by the local alignment against different databases, were subjected to further bioinformatic analyses including three-dimensional (3D) structure prediction by AlphaFold. AlphaFold models of phage lysis proteins were consistent with the published X-ray crystal structures, suggesting the presence of T4-like and P1/P2-like bacteriophage lysis proteins in KP1 and KP12, respectively. By providing the primary sequence information, this study contributes novel bacteriophages for research and development pipelines of phage therapy that ultimately, cater to the unmet clinical and industrial needs against K. pneumoniae pathogens.

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“…Although the covalent conjugation of the cationic amphiphilic KFF peptide and the anionic ASOs might lead to the formation of aggregates due to charge-charge interactions, we chose KFF for three reasons. First, KFF has previously been used as carrier for different ASO modalities (such as PNA, PMO and LNA) and has been successfully applied to different bacterial species (3,6,23,54). Second, in a mini-library of different CPP-ASOs, KFF delivered ASOs had the smallest global effect on the bacterial transcriptome (30).…”

Section: Methodsmentioning

confidence: 99%

“…Short single-stranded antisense oligomers (ASOs) that inhibit the translation of essential bacterial genes are promising candidates (1,2). They have been shown to be effective antibacterials against a range of pathogens (3)(4)(5)(6)(7)(8). Their efficacy has also been validated in animal models of infection with Escherichia coli, Pseudomonas aeruginosa and Klebsiella pneumoniae either as monotherapy or in combinations with other antibiotics (9)(10)(11)(12).…”

Section: Introductionmentioning

confidence: 99%

A side-by-side comparison of peptide-delivered antisense antibiotics employing different nucleotide mimics

Ghosh

Popella²,

Dhamodharan

et al. 2023

Preprint

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Antisense oligomer (ASO)-based antibiotics that target mRNAs of essential bacterial genes have great potential for counteracting antimicrobial resistance and for precision microbiome editing. To date, the development of such antisense antibiotics has primarily focused on using phosphorodiamidate morpholino (PMO) and peptide nucleic acid (PNA) backbones, largely ignoring the growing number of chemical modalities that have spurred the success of ASO-based human therapy. Here, we directly compare the activities of seven chemically distinct 10mer ASOs, all designed to target the essential gene acpP upon delivery with a KFF-peptide carrier into Salmonella. Our systematic analysis of PNA, PMO, phosphorothioate-modified DNA (PTO), 2′-methylated RNA (RNA-OMe), 2′-methoxyethylated RNA (RNA-MOE), 2′-fluorinated RNA (RNA-F) and 2′-4′-locked RNA (LNA) is based on a variety of in vitro and in vivo methods to evaluate ASO uptake, target pairing and inhibition of bacterial growth. Our data show that only PNA and PMO are efficiently delivered by the KFF peptide into Salmonella to inhibit bacterial growth. Nevertheless, the strong target binding affinity and in vitro translational repression activity of LNA and RNA-MOE make them promising modalities for antisense antibiotics that will require the identification of an effective carrier.

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Antisense peptide nucleic acid inhibits the growth of KPC-producing Klebsiella pneumoniae strain

Cited by 10 publications

References 38 publications

Selected strategies to fight pathogenic bacteria

Selected strategies to fight pathogenic bacteria

Characterization of Klebsiella pneumoniae bacteriophages, KP1 and KP12, with deep learning-based structure prediction

A side-by-side comparison of peptide-delivered antisense antibiotics employing different nucleotide mimics

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