Peptide nucleic acid antisense oligomers open an avenue for developing novel antibacterial molecules

Ghosal, Anubrata

doi:10.3855/jidc.9159

Cited by 7 publications

(7 citation statements)

References 27 publications

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“…In this review, we have summarized and presented these strategies. In the last decade, a few reviews on PNA antibacterial applications have been published, e.g., [14][15][16][17][18]. We have updated this information, specifically focusing on PNA modifications, structural data for PNA-involving complexes, antibacterial targets, and transport into bacterial cells.…”

Section: Introductionmentioning

confidence: 99%

Antibacterial Peptide Nucleic Acids—Facts and Perspectives

et al. 2020

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Antibiotic resistance is an escalating, worldwide problem. Due to excessive use of antibiotics, multidrug-resistant bacteria have become a serious threat and a major global healthcare problem of the 21st century. This fact creates an urgent need for new and effective antimicrobials. The common strategies for antibiotic discovery are based on either modifying existing antibiotics or screening compound libraries, but these strategies have not been successful in recent decades. An alternative approach could be to use gene-specific oligonucleotides, such as peptide nucleic acid (PNA) oligomers, that can specifically target any single pathogen. This approach broadens the range of potential targets to any gene with a known sequence in any bacterium, and could significantly reduce the time required to discover new antimicrobials or their redesign, if resistance arises. We review the potential of PNA as an antibacterial molecule. First, we describe the physicochemical properties of PNA and modifications of the PNA backbone and nucleobases. Second, we review the carriers used to transport PNA to bacterial cells. Furthermore, we discuss the PNA targets in antibacterial studies focusing on antisense PNA targeting bacterial mRNA and rRNA.

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Section: Introductionmentioning

confidence: 99%

Antibacterial Peptide Nucleic Acids—Facts and Perspectives

et al. 2020

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“…Attempts to develop novel antimicrobials have also been made, but many have failed, and the potential emergence of drug resistance remains [ 19 ]. Scientists have searched for alternatives to overcome the shortcomings of conventional antimicrobials, and one of the approaches is to design ASPs conjugated to a CPP that can complementarily bind to RNA expressed by their targets, which in turn affect translation or post-transcriptional processing [ 8 9 10 12 ]. Previously, two antisense P-PNAs targeting the essential genes in S. aureus were developed: ASP-cmk and ASP-deoD.…”

Section: Discussionmentioning

confidence: 99%

“…Antisense binding of PNA to the target nucleic acids silences their transcription or translation, preventing their expression and impeding their biological functions [ 8 9 ]. PNAs have been assessed as alternatives to antimicrobials designed to target essential genes [ 10 11 ]. PNAs are often conjugated with a cell-penetrating peptide (CPP), such as the KFF motif peptide and its variants, for efficient delivery across the bacterial membrane [ 12 13 ].…”

Section: Introductionmentioning

confidence: 99%

Combined antimicrobial effect of two peptide nucleic acids against Staphylococcus aureus and S. pseudintermedius veterinary isolates

Kim,

Lee,

Lee

et al. 2024

J Vet Sci

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Background Staphylococcus aureus and S. pseudintermedius are the major etiological agents of staphylococcal infections in humans, livestock, and companion animals. The misuse of antimicrobial drugs has led to the emergence of antimicrobial-resistant Staphylococcus spp., including methicillin-resistant S. aureus (MRSA) and methicillin-resistant S. pseudintermedius (MRSP). One novel therapeutic approach against MRSA and MRSP is a peptide nucleic acid (PNA) that can bind to the target nucleotide strands and block expression. Previously, two PNAs conjugated with cell-penetrating peptides (P-PNAs), antisense PNA (ASP)-cmk and ASP-deoD, targeting two essential genes in S. aureus , were constructed, and their antibacterial activities were analyzed. Objectives This study analyzed the combined antibacterial effects of P-PNAs on S. aureus and S. pseudintermedius clinical isolates. Methods S. aureus ATCC 29740 cells were treated simultaneously with serially diluted ASP-cmk and ASP-deoD, and the minimal inhibitory concentrations (MICs) were measured. The combined P-PNA mixture was then treated with S. aureus and S. pseudintermedius veterinary isolates at the determined MIC, and the antibacterial effect was examined. Results The combined treatment of two P-PNAs showed higher antibacterial activity than the individual treatments. The MICs of two individual P-PNAs were 20 and 25 μM, whereas that of the combined treatment was 10 μM. The application of a combined treatment to clinical Staphylococcus spp. revealed S. aureus isolates to be resistant to P-PNAs and S. pseudintermedius isolates to be susceptible. Conclusions These observations highlight the complexity of designing ASPs with high efficacy for potential applications in treating staphylococcal infections in humans and animals.

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“… − The most common PNA ( 1 ) consists of nucleobases bonded to a highly flexible N -(2-aminoethyl) glycine ( aeg ) backbone that does not occur naturally. The lack of negative charge on the pseudopeptide backbone of aeg PNA 1 facilitates strong binding to complementary oligonucleotides, and the synthetic backbone conveys resistance to enzymatic degradation. − These unique properties make aeg PNAs ideal molecules for antisense applications in addition to probes for molecular diagnostics. − However, aeg PNAs are limited by poor cellular uptake and low aqueous solubility . Numerous efforts have been made to modify aeg PNA to address these concerns, − and the addition of charged groups either to the backbone or the ends of aeg PNA will improve aqueous solubility and cellular uptake via mechanisms typically involving endocytosis.…”

Section: Introductionmentioning

confidence: 99%

Variation of Tetrahydrofurans in Thyclotides Enhances Oligonucleotide Binding and Cellular Uptake of Peptide Nucleic Acids

Zheng

Clausse

Amarasekara

et al. 2023

JACS Au

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Selective incorporation of conformational constraints into thyclotides can be used to modulate their binding to complementary oligonucleotides, increase polarity, and optimize uptake into HCT116 cells without assistance from moieties known to promote cell uptake. The X-ray structure and biophysical studies of a thyclotide–DNA duplex reveal that incorporation of tetrahydrofurans into an aegPNA backbone promotes a helical conformation that enhances binding to complementary DNA and RNA. Selective incorporation of tetrahydrofurans into the aegPNA backbone allows polarity to be increased incrementally so that uptake into HCT116 cells can be optimized. The enhanced binding, polarity, and cellular uptake properties of thyclotides were used to demonstrate effective inhibition of microRNA-21 in HCT116 cells.

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Peptide nucleic acid antisense oligomers open an avenue for developing novel antibacterial molecules

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Cited by 7 publications

References 27 publications

Antibacterial Peptide Nucleic Acids—Facts and Perspectives

Antibacterial Peptide Nucleic Acids—Facts and Perspectives

Combined antimicrobial effect of two peptide nucleic acids against Staphylococcus aureus and S. pseudintermedius veterinary isolates

Variation of Tetrahydrofurans in Thyclotides Enhances Oligonucleotide Binding and Cellular Uptake of Peptide Nucleic Acids

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