Dataset Information

Intercepting biological messages: Antibacterial molecules targeting nucleic acids during interbacterial conflicts.

ABSTRACT: Bacteria live in polymicrobial communities and constantly compete for resources. These organisms have evolved an array of antibacterial weapons to inhibit the growth or kill competitors. The arsenal comprises antibiotics, bacteriocins, and contact-dependent effectors that are either secreted in the medium or directly translocated into target cells. During bacterial antagonistic encounters, several cellular components important for life become a weak spot prone to an attack. Nucleic acids and the machinery responsible for their synthesis are well conserved across the tree of life. These molecules are part of the information flow in the central dogma of molecular biology and mediate long- and short-term storage for genetic information. The aim of this review is to summarize the diversity of antibacterial molecules that target nucleic acids during antagonistic interbacterial encounters and discuss their potential to promote the emergence antibiotic resistance.

SUBMITTER: Hespanhol JT

PROVIDER: S-EPMC9990079 | biostudies-literature | 2023

REPOSITORIES: biostudies-literature

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Intercepting biological messages: Antibacterial molecules targeting nucleic acids during interbacterial conflicts.

Hespanhol Julia Takuno JT Karman Lior L Sanchez-Limache Daniel Enrique DE Bayer-Santos Ethel E

Genetics and molecular biology 20230306 1 Suppl 2

Bacteria live in polymicrobial communities and constantly compete for resources. These organisms have evolved an array of antibacterial weapons to inhibit the growth or kill competitors. The arsenal comprises antibiotics, bacteriocins, and contact-dependent effectors that are either secreted in the medium or directly translocated into target cells. During bacterial antagonistic encounters, several cellular components important for life become a weak spot prone to an attack. Nucleic acids and the ...[more]

PMID: 36880694

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Project description:Liposomal spherical nucleic acids (LSNAs) are a class of nanomaterial used broadly for biomedical applications. Their intrinsic capacity to rapidly enter cells and engage cell surface and intracellular ligands stems from their unique three-dimensional architecture, which consists of densely packed and uniformly oriented oligonucleotides on the surface of a liposomal core. Such structures are promising for therapeutics because they can carry chemical cargo within the lipid core in addition to the nucleic acids that define them, in principle enabling delivery of multiple signals to a single cell. On the basis of these traits, we have designed novel dual-targeting LSNAs that deliver a nucleic acid specific for TLR9 inhibition and a small molecule (TAK-242) that inhibits TLR4. Toll-like receptors (TLRs) play a large role in pathogen recognition and disease initiation, and TLR subtypes are differentially located within the lipid membranes of the cell surface and within intracellular endosomes. Oftentimes, in acute or chronic inflammatory conditions, multiple TLRs are activated, leading to stimulation of distinct, and sometimes overlapping, downstream pathways. As such, these inflammatory conditions may respond to attenuation of more than one initiating receptor. We show that dual targeting LSNAs, comprised of unilamellar liposomal cores, the INH-18 oligonucleotide sequence, and TAK-242 robustly inhibit TLR-9 and TLR-4 respectively, in engineered TLR reporter cells and primary mouse peritoneal macrophages. Importantly, the LSNAs exhibit up to a 10- and a 1000-fold increase, respectively, in TLR inhibition compared to the linear sequence and TAK-242 alone. Moreover, the timing of delivery is shown to be a critical factor in effecting TLR-inhibition, with near-complete TLR-4 inhibition occurring when cells were pretreated with SNAs for 4 h prior to stimulation. The most pronounced effect observed from this approach is the benefit of delivering the small molecule within the SNA via the receptor-mediated internalization pathway common to SNAs.

Dataset Information

Intercepting biological messages: Antibacterial molecules targeting nucleic acids during interbacterial conflicts.

Publications

Intercepting biological messages: Antibacterial molecules targeting nucleic acids during interbacterial conflicts.

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