Using Sequence-Specific Oligonucleotides To Inhibit Bacterial rRNA

Trylska, Joanna; Thoduka, Sapna G.; Dabrowska, Zofia

doi:10.1021/cb400163t

Cited by 15 publications

(10 citation statements)

References 92 publications

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“…Many antibiotics exert their antimicrobial effects by binding to bacterial ribosome and interfering with protein synthesis (Figure 5) [136]. Three-dimensional structures of bacterial ribosomes were determined by X-ray crystallography showing that rRNA could be a promising target for the PNA oligomers.…”

Section: Ribosome As a Target For Antibacterial Pnamentioning

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: Ribosome As a Target For Antibacterial Pnamentioning

confidence: 99%

Antibacterial Peptide Nucleic Acids—Facts and Perspectives

et al. 2020

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“…The thermal stability of PNA–RNA duplexes was found to be higher than that of PNA–DNA duplexes . To complement many antisense applications of PNA targeting mRNA but also rRNA , and past thermodynamic studies performed on PNA complexes with DNA, we focus here on the thermal stability of PNA complexes with RNA.…”

Section: Introductionmentioning

confidence: 99%

Thermal Stability of Peptide Nucleic Acid Complexes

et al. 2019

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Peptide nucleic acid (PNA) is a neutral nucleic acid analogue that base pairs with itself and natural nucleic acids. PNA–nucleic acid complexes are more thermally stable than the corresponding complexes of natural nucleic acids. In addition, PNA is biostable and thus used in many antisense and antigene applications to block functional RNA or DNA via sequence-specific interactions. We have recently developed force field parameters for molecular dynamics (MD) simulations of PNA and PNA-involving duplexes with natural nucleic acids. In this work, we provide the first application of this force field to biologically relevant PNA sequences and their complexes with RNA. We investigated thermal stabilities of short PNA–PNA, PNA–RNA, and RNA–RNA duplexes using UV-monitored thermal denaturation experiments and MD simulations at ambient and elevated temperatures. The simulations show a two-state melting transition and reproduce the thermal stability from melting experiments, with PNA–PNA being the most and RNA–RNA the least stable. The PNA–PNA duplex also displays the highest activation energy for melting. The atomistic details of unfolding of PNA duplexes suggest that all PNA–PNA bases melt concomitantly, whereas the RNA–RNA and PNA–RNA are destabilized from the termini toward the central part of the duplexes.

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“…nascent peptide exit, tRNA binding, peptidyl transferase targeting, etc. This results in mismatch of amino acids, hindered translocation and premature dissociation of peptidyl tRNA from ribosomes, which reduced ribosomal protein translation, and eventually impact ribosome assembly and cause lethal defects in bacterial protein synthesis 27 , 28 . It has been well accepted that mitochondrial evolutionally have a bacterial ancestry.…”

Section: Introductionmentioning

confidence: 99%

Antibiotic Azithromycin inhibits brown/beige fat functionality and promotes obesity in human and rodents

Yu¹,

Chen²,

Zhang³

et al. 2022

Theranostics

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Obesity, a metabolic disease caused by multiple factors, has become a global health problem. In addition to nutrient intake and sedentary lifestyle, environmental pollutants exposure has been shown to be involved in obesity epidemics. Antibiotics, a new type of environmental pollutant, have been widely used in animal husbandry, aquaculture and microorganism. However, the effects of antibiotics exposure on fat metabolism and metabolic diseases are largely unknown. Methods: We screened major types of antibiotics to examine their effects on the differentiation capacity and thermogenic functionality of brown and beige adipocytes, and found that azithromycin, one major kind of macrolide antibiotics suppressed brown and beige adipocyte functionality. We thus examined azithromycin accretion in adipose tissues of obese patients that correlates with BMI by high performance liquid chromatography-tandem mass spectrometry and systematically explore the influences of azithromycin on adiposity and metabolic performance in mice under high diet. Results: Azithromycin (macrolides) inhibits the mitochondrial and thermogenic gene programs of brown and beige adipocytes, thus disrupting their mitochondrial function and thermogenic response. Consistently, azithromycin treatment are more prone to diet-induced obesity in mice, and this was associated with impaired energy expenditure. Importantly, azithromycin is more accumulated in adipose tissue of obese patients and correlates with BMI and body weight. Mechanistically, we found that azithromycin inhibits mitochondria respiratory complex I protein levels and increases reactive oxidative species (ROS) levels, which causes damage of mitochondrial function in brown and beige adipocytes. The deleterious effects of azithromycin can be ameliorated by antioxidant N-acetyl-L-cysteine. Conclusions: Taken together, this work highlights the possible role of azithromycin in obesity epidemic and presents strategies for safe applications of antibiotics in the future.

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Using Sequence-Specific Oligonucleotides To Inhibit Bacterial rRNA

Cited by 15 publications

References 92 publications

Antibacterial Peptide Nucleic Acids—Facts and Perspectives

Antibacterial Peptide Nucleic Acids—Facts and Perspectives

Thermal Stability of Peptide Nucleic Acid Complexes

Antibiotic Azithromycin inhibits brown/beige fat functionality and promotes obesity in human and rodents

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