111 research outputs found
Fragments of the nonlytic proline-rich antimicrobial peptide Bac5 kill Escherichia coli cells by inhibiting protein synthesis
Unlike most antimicrobial peptides (AMPs), the main mode of action of
the subclass of proline-rich antimicrobial peptides (PrAMPs) is not based on disruption
of the bacterial membrane. Instead, PrAMPs exploit the inner membrane transporters
SbmA and YjiL/MdtM to pass through the bacterial membrane and enter the
cytosol of specific Gram-negative bacteria, where they exert an inhibitory effect on
protein synthesis. Despite sharing a high proline and arginine content with other
characterized PrAMPs, the PrAMP Bac5 has a low sequence identity with them. Here
we investigated the mode of action of three N-terminal Bac5 fragments, Bac5(1-15),
Bac5(1-25), and Bac5(1-31). We show that Bac5(1-25) and Bac5(1-31) retained excellent
antimicrobial activity toward Escherichia coli and low toxicity toward eukaryotic
cells, whereas Bac5(1-15) was inactive. Bac5(1-25) and Bac5(1-31) inhibited bacterial
protein synthesis in vitro and in vivo. Competition assays suggested that the binding
site of Bac5 is within the ribosomal tunnel, where it prevents the transition from the
initiation to the elongation phase of translation, as reported for other PrAMPs, such
as the bovine PrAMP Bac7. Surprisingly, unlike Bac7, Bac5(1-25) exhibited speciesspecific
inhibition, being an excellent inhibitor of protein synthesis on E. coli ribosomes
but a poor inhibitor on Thermus thermophilus ribosomes. This indicates that
while Bac5 most likely has an overlapping binding site with Bac7, the mode of interaction
is distinct, suggesting that Bac5 fragments may be interesting alternative lead
compounds for the development of new antimicrobial agents
The dolphin proline-rich antimicrobial peptide Tur1A inhibits protein synthesis by targeting the bacterial ribosome
Proline-rich antimicrobial peptides (PrAMPs) internalize into susceptible bacteria using specific transporters and interfere with protein synthesis and folding. To date, mammalian PrAMPs have so far only been identified in artiodactyls. Since cetaceans are co-phyletic with artiodactyls, we mined the genome of the bottlenose dolphin Tursiops truncates, leading to the identification of two PrAMPs, Tur1A and Tur1B. Tur1A, which is orthologous to the bovine PrAMP Bac7, is internalized into E. coli without damaging the membranes using the inner membrane transporters SbmA and YjiL/MdM. Furthermore, like Bac7, Tur1A also inhibits bacterial protein synthesis by binding to the ribosome and blocking the transition from the initiation to the elongation phase. By contrast, Tur1B is a poor inhibitor of protein synthesis and may utilize another mechanism of action. An X-ray structure of Tur1A bound within the ribosomal exit tunnel provides a basis to develop these peptides as novel antimicrobial agents
Myticalins: A novel multigenic family of linear, cationic antimicrobial peptides from marine mussels (Mytilus spp.)
The application of high-throughput sequencing technologies to non-model organisms has brought new opportunities for the identification of bioactive peptides from genomes and transcriptomes. From this point of view, marine invertebrates represent a potentially rich, yet largely unexplored resource for de novo discovery due to their adaptation to diverse challenging habitats. Bioinformatics analyses of available genomic and transcriptomic data allowed us to identify myticalins, a novel family of antimicrobial peptides (AMPs) from the mussel Mytilus galloprovincialis, and a similar family of AMPs from Modiolus spp., named modiocalins. Their coding sequence encompasses two conserved N-terminal (signal peptide) and C-terminal (propeptide) regions and a hypervariable central cationic region corresponding to the mature peptide. Myticalins are taxonomically restricted to Mytiloida and they can be classified into four subfamilies. These AMPs are subject to considerable interindividual sequence variability and possibly to presence/absence variation. Functional assays performed on selected members of this family indicate a remarkable tissue-specific expression (in gills) and broad spectrum of activity against both Gram-positive and Gram-negative bacteria. Overall, we present the first linear AMPs ever described in marine mussels and confirm the great potential of bioinformatics tools for the de novo discovery of bioactive peptides in non-model organisms
The Relation Between Activity and Environment in Compact Groups of Galaxies
We present the results of the classification of spectral activity types for
193 galaxies from a new sample of 49 compact groups of galaxies in the southern
hemisphere (SCGs). This sample was selected in automated fashion from a
digitized galaxy catalogue, covering an area of ~5200 sq deg, around the South
Galactic Pole. It is complete up to m ~14.5 in b_j for the brightest galaxy of
the group.
The spectral analysis of the SCG galaxies confirms the results previously
obtained for a smaller sample of Hickson's compact groups (HCG). We confirm the
luminosity-activity and morphology-activity relations, as well as the
predominance of AGNs (41% of SCGs galaxies). We verified also that the number
of early-type non-emission-line galaxies increases with the number of members
in the group.
The SCGs contain more star-forming galaxies (SFGs) and less non-emission-line
galaxies than HCGs, which suggests that they probe a wider range of physical
properties. The SFGs are composed in majority of HII Nucleus Galaxies, which
have less intense star formation than starburst galaxies. The star formation
activity in SCGs is, consequently, remarkably low. The SFGs show also evidence
for nuclear activity. If these results are further confirmed, 70% of the
galaxies in SCGs would then have an active nucleus, making these systems
remarkably rich in AGNs. Curiously, however, this characteristic of CGs
generally excludes Seyfert 1 galaxies.(Abridged)Comment: 53 pages, Latex, 9 encapsulated postscript figures, Accepted for
publication in The Astronomical Journa
Structure of the mammalian antimicrobial peptide Bac7(1-16) bound within the exit tunnel of a bacterial ribosome
Proline-rich antimicrobial peptides (PrAMPs) produced as part of the innate immune response of animals, insects and plants represent a vast, untapped resource for the treatment of multidrug-resistant bacterial infections. PrAMPs such as oncocin or bactenecin-7 (Bac7) interact with the bacterial ribosome to inhibit translation, but their supposed specificity as inhibitors of bacterial rather than mammalian protein synthesis remains unclear, despite being key to developing drugs with low toxicity. Here, we present crystal structures of the Thermus thermophilus 70S ribosome in complex with the first 16 residues of mammalian Bac7, as well as the insect-derived PrAMPs metalnikowin I and pyrrhocoricin. The structures reveal that the mammalian Bac7 interacts with a similar region of the ribosome as insect-derived PrAMPs. Consistently, Bac7 and the oncocin derivative Onc112 compete effectively with antibiotics, such as erythromycin, which target the ribosomal exit tunnel. Moreover, we demonstrate that Bac7 allows initiation complex formation but prevents entry into the elongation phase of translation, and show that it inhibits translation on both mammalian and bacterial ribosomes, explaining why this peptide needs to be stored as an inactive pro-peptide. These findings highlight the need to consider the specificity of PrAMP derivatives for the bacterial ribosome in future drug development efforts
Peptide inhibitors of bacterial protein synthesis with broad spectrum and SbmA-independent bactericidal activity against clinical pathogens.
Proline-rich antimicrobial peptides (PrAMPs) are promising lead compounds for developing new antimicrobials, however their narrow spectrum of action is limiting. PrAMPs kill bacteria binding to their ribosomes and inhibiting protein synthesis. In this study, 133 derivatives of the PrAMP Bac7(1-16) were synthesized to identify the crucial residues for ribosome inactivation and antimicrobial activity. Then, five new Bac7(1-16) derivatives were conceived and characterized by antibacterial and membrane permeabilization assays, by X-ray crystallography and molecular dynamics simulations. Some derivatives displayed broad spectrum activity, encompassing Escherichia coli, Klebsiella pneumoniae, Acinetobacter baumanii, Pseudomonas aeruginosa and Staphylococcus aureus. Two peptides out of five, acquired a weak membrane-perturbing activity, while maintaining the ability to inhibit protein synthesis. These derivatives became independent of the SbmA transporter, commonly used by native PrAMPs, suggesting that they obtained a novel route to enter bacterial cells. PrAMP-derived compounds could become new-generation antimicrobials to combat the antibiotic-resistant pathogens
Machine learning for molecular and materials science
Here we summarize recent progress in machine learning for the chemical sciences. We outline machine-learning techniques that are suitable for addressing research questions in this domain, as well as future directions for the field. We envisage a future in which the design, synthesis, characterization and application of molecules and materials is accelerated by artificial intelligence.</p
Genes with high penetrance for syndromic and non-syndromic autism typically function within the nucleus and regulate gene expression
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Thirty years of density functional theory in computational chemistry: An overview and extensive assessment of 200 density functionals
In the past 30 years, Kohn–Sham density functional theory has emerged as the most popular electronic structuremethod in computational chemistry. To assess the ever-increasing number of approximate exchange-correlation functionals, this review benchmarks a total of 200 density functionals on a molecular database (MGCDB84) of nearly 5000 data points. The database employed, provided as Supplemental Data, is comprised of 84 data-sets and contains non-covalent interactions, isomerisation energies, thermochemistry, and barrier heights. In addition, the evolution of nonempirical and semi-empirical density functional design is reviewed, and guidelines are provided for the proper and effective use of density functionals. The most promising functional considered is ωB97M-V, a range-separated hybrid meta-GGA with VV10 nonlocal correlation, designed using a combinatorial approach. From the local GGAs, B97-D3, revPBE-D3, and BLYP-D3 are recommended, while from the local meta-GGAs, B97M-rV is the leading choice, followed by MS1-D3 and M06-LD3. The best hybrid GGAs are ωB97X-V, ωB97X-D3, and ωB97X-D, while useful hybrid meta-GGAs (besides ωB97M-V) include ωM05-D, M06-2X-D3, and MN15. Ultimately, today’s state-of-the-art functionals are close to achieving the level of accuracy desired for a broad range of chemical applications, and the principal remaining limitations are associated with systems that exhibit significant selfinteraction/ delocalisation errors and/or strong correlation effects
Characterization of cetacean proline-rich antimicrobial peptides displaying activity against eskape pathogens
Proline-rich antimicrobial peptides (PrAMPs) may be a valuable weapon against multi-drug resistant pathogens, combining potent antimicrobial activity with low cytotoxicity. We have identified novel PrAMPs from five cetacean species (cePrAMPs), and characterized their potency, mechanism of action and in vitro cytotoxicity. Despite the homology between the N-terminal of cePrAMPs and the bovine PrAMP Bac7, some differences emerged in their sequence, activity spectrum and mode of action. CePrAMPs with the highest similarity with the Bac7(1-35) fragment inhibited bacterial protein synthesis without membrane permeabilization, while a second subgroup of cePrAMPs was more membrane-active but less efficient at inhibiting bacterial translation. Such differences may be ascribable to differences in presence and positioning of Trp residues and of a conserved motif seemingly required for translation inhibition. Unlike Bac7(1-35), which requires the peptide transporter SbmA for its uptake, the activity of cePrAMPs was mostly independent of SbmA, regardless of their mechanism of action. Two peptides displayed a promisingly broad spectrum of activity, with minimal inhibiting concentration MIC 64 4 \ub5M against several bacteria of the ESKAPE group, including Pseudomonas aeruginosa and Enterococcus faecium. Our approach has led us to discover several new peptides; correlating their sequences and mechanism of action will provide useful insights for designing optimized future peptide-based antibiotics
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