Novel Anion Liposome-Encapsulated Antisense Oligonucleotide Restores Susceptibility of Methicillin-Resistant<i>Staphylococcus aureus</i>and Rescues Mice from Lethal Sepsis by Targeting<i>mecA</i>

Meng, Jingru; Wang, Hui; Zheng, Hui; Chen, Tao; Fu, Jingguo; Ma, Xue; He, Gong-Hao; Xue, Xiaoyan; Jia, Min; Luo, Xiaoxing

doi:10.1128/aac.01542-08

Cited by 69 publications

(68 citation statements)

References 42 publications

(41 reference statements)

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“…Therefore, MRSA presents a formidable challenge for exploring new therapeutic strategies and antibiotics with novel mechanisms of action, distinct from those of existing antibiotics. Data from our research and the work of others have proven that antisense oligonucleotides provide a revolutionary approach to treating infections due to multidrug-resistant pathogens (13,24,25).…”

Section: Discussionmentioning

confidence: 99%

Antisense Growth Inhibition of Methicillin-Resistant Staphylococcus aureus by Locked Nucleic Acid Conjugated with Cell-Penetrating Peptide as a Novel FtsZ Inhibitor

Meng

et al. 2015

Antimicrob Agents Chemother

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b Methicillin-resistant Staphylococcus aureus (MRSA) infections are becoming increasingly difficult to treat, owing to acquired antibiotic resistance. The emergence and spread of MRSA limit therapeutic options and require new therapeutic strategies, including novel MRSA-active antibiotics. Filamentous temperature-sensitive protein Z (FtsZ) is a highly conserved bacterial tubulin homologue that is essential for controlling the bacterial cell division process in different species of S. aureus. We conjugated a locked nucleic acid (LNA) that targeted ftsZ mRNA with the peptide (KFF) 3 K, to generate peptide-LNA (PLNA). The present study aimed to investigate whether PLNA could be used as a novel antibacterial agent. PLNA787, the most active agent synthesized, exhibited promising inhibitory effects on four pathogenic S. aureus strains in vitro. PLNA787 inhibited bacterial growth and resolved lethal Mu50 infections in epithelial cell cultures. PLNA787 also improved the survival rates of Mu50-infected mice and was associated with reductions of bacterial titers in several tissue types. The inhibitory effects on ftsZ mRNA and FtsZ protein expression and inhibition of the bacterial cell division process are considered to be the major mechanisms of PLNA. PLNA787 demonstrated activity against MRSA infections in vitro and in vivo. Our findings suggest that ftsZ mRNA is a promising new target for developing novel antisense antibiotics. Staphylococcus aureus, particularly methicillin-resistant S. aureus (MRSA), is one of the most prominent pathogens known to pose a severe threat to human health (1). Statistical data from recent epidemiological studies indicate that the prevalence of MRSA is spreading globally. MRSA, particularly community-associated MRSA, has increased markedly in prevalence and continues to pose a significant public health challenge (2-4). ␤-Lactam antibiotics are most effective against infections caused by S. aureus. However, widespread use of ␤-lactam antibiotics has led to increasing prevalence of drug-resistant S. aureus; thus, the therapeutic options available for treating MRSA infections have become seriously limited, and MRSA infections are becoming increasingly difficult to treat. Indeed, MRSA has become resistant to the entire class of ␤-lactam antibiotics and to most available antibiotics (5-7). Although linezolid, daptomycin, and telavancin are new drugs to treat MRSA infections, the development of new and non-cross-resistant antibacterial agents with novel mechanisms of action against MRSA is still needed.Antisense oligonucleotides are potential therapeutic agents for prevention of the translation of essential genes at the mRNA level with antisense nucleic acid analogues, such as phosphorothioate oligodeoxynucleotides (PS-ODNs), peptide-nucleic acids (PNAs), locked nucleic acids (LNAs), and phosphorodiamidate morpholino oligomers (8, 9). LNAs are nucleic acid analogues in which the ribose ring is locked by a 2=-O,4=-C-methylene bridge. LNA oligomers have high affinity for RNA or DNA targets, are qu...

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Section: Discussionmentioning

confidence: 99%

Antisense Growth Inhibition of Methicillin-Resistant Staphylococcus aureus by Locked Nucleic Acid Conjugated with Cell-Penetrating Peptide as a Novel FtsZ Inhibitor

Meng

et al. 2015

Antimicrob Agents Chemother

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“…Thus, this strategy may raise the bar for infecting strains to develop resistance, potentially reducing future burdens of antimicrobial-resistant P. aeruginosa. Delivery of antisense oligonucleotides (AS-ODNs) via anionic liposomes has been successful in several bacterial species (72)(73)(74) and may provide a novel means for targeting sRNAs, such as PrrF and PrrH, to block virulence. Future work determining how each of the ⌬prrF1,2 mutant phenotypes contributes to P. aeruginosa virulence attenuation will be critical for the development of AS-ODN molecules that effectively block pathogenesis.…”

Section: Discussionmentioning

confidence: 99%

The prrF -Encoded Small Regulatory RNAs Are Required for Iron Homeostasis and Virulence of Pseudomonas aeruginosa

et al. 2015

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Pseudomonas aeruginosa is an opportunistic pathogen that requires iron to cause infection, but it also must regulate the uptake of iron to avoid iron toxicity. The iron-responsive PrrF1 and PrrF2 small regulatory RNAs (sRNAs) are part of P. aeruginosa's iron regulatory network and affect the expression of at least 50 genes encoding iron-containing proteins. The genes encoding the PrrF1 and PrrF2 sRNAs are encoded in tandem in P. aeruginosa, allowing for the expression of a distinct, heme-responsive sRNA named PrrH that appears to regulate genes involved in heme metabolism. Using a combination of growth, mass spectrometry, and gene expression analysis, we showed that the ⌬prrF1,2 mutant, which lacks expression of the PrrF and PrrH sRNAs, is defective for both iron and heme homeostasis. We also identified phuS, encoding a heme binding protein involved in heme acquisition, and vreR, encoding a previously identified regulator of P. aeruginosa virulence genes, as novel targets of prrF-mediated heme regulation. Finally, we showed that the prrF locus encoding the PrrF and PrrH sRNAs is required for P. aeruginosa virulence in a murine model of acute lung infection. Moreover, we showed that inoculation with a ⌬prrF1,2 deletion mutant protects against future challenge with wild-type P. aeruginosa. Combined, these data demonstrate that the prrF-encoded sRNAs are critical regulators of P. aeruginosa virulence. Pseudomonas aeruginosa is a ubiquitous Gram-negative bacterium and versatile opportunistic pathogen. Iron is required for P. aeruginosa virulence (1-6) and is obtained through several mechanisms. In anaerobic environments, iron in its ferrous form is freely diffusible through the outer membrane (OM) and transported into the cytoplasm by the Feo inner membrane transport system (7,8). However, the insolubility of ferric iron in aerobic environments limits accessibility to this nutrient. Moreover, the sequestration of iron by host proteins creates a substantial barrier to infection (9, 10). To overcome this barrier, P. aeruginosa synthesizes and secretes two siderophores, pyoverdine and pyochelin, which scavenge ferric iron (1-4). P. aeruginosa can also acquire heme, an abundant source of iron in the human host (11). Once internalized, heme is sequestered by the cytosolic PhuS heme chaperone (12). PhuS transfers heme to the iron-regulated HemO heme oxygenase, which degrades heme to biliverdin, releasing carbon monoxide and iron (13,14). Several studies have shown that iron acquisition is essential for P. aeruginosa virulence (1-5) and biofilm formation (15-17), demonstrating the central role of this element in P. aeruginosa pathogenesis.Despite its essentiality, iron and heme can be toxic due to their ability to catalyze the formation of reactive oxygen species. Thus, to maintain iron homeostasis, P. aeruginosa must be able to not only acquire iron but also regulate uptake of iron and heme from the environment, as well as iron use and storage. Expression of genes encoding iron and heme uptake systems in P. aeruginosa is ...

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“…Meng ve ark. (36) yaptığı çalışmada, lipozom içerisinde taşınan fosforotioate oligomerleri ile mecA geni susturulmaya çalışılmıştır. Yüksek derecece korunmuş bir bölge olan ve metisilin direncinden sorumlu olan bu genin hedef alınmasıyla, izolatların beta laktam antibiyotiklere daha duyarlı hâle gelmesi, oksasilinle tamamen inhibe edilebilmesi sağlanmıştır.…”

Section: Yılında çOklu Ilaç Direnci (çİd) Gösterenunclassified

Antisense Oligonucleotids and Antibacterial Use

Tekintaş¹,

Dora²,

Limoncu³

2016

TMCD

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Novel Anion Liposome-Encapsulated Antisense Oligonucleotide Restores Susceptibility of Methicillin-ResistantStaphylococcus aureusand Rescues Mice from Lethal Sepsis by TargetingmecA

Cited by 69 publications

References 42 publications

Antisense Growth Inhibition of Methicillin-Resistant Staphylococcus aureus by Locked Nucleic Acid Conjugated with Cell-Penetrating Peptide as a Novel FtsZ Inhibitor

Antisense Growth Inhibition of Methicillin-Resistant Staphylococcus aureus by Locked Nucleic Acid Conjugated with Cell-Penetrating Peptide as a Novel FtsZ Inhibitor

The prrF -Encoded Small Regulatory RNAs Are Required for Iron Homeostasis and Virulence of Pseudomonas aeruginosa

Antisense Oligonucleotids and Antibacterial Use

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