BamA-targeted antimicrobial peptide design for enhanced efficacy and reduced toxicity.

The emergence of drug-resistant superbugs has necessitated a pressing need for innovative antibiotics. Antimicrobial peptides (AMPs) have demonstrated broad-spectrum antibacterial activity, reduced susceptibility to resistance, and immunomodulatory effects, rendering them promising for combating drug-resistant microorganisms. This study employed computational simulation methods to screen and design AMPs specifically targeting ESKAPE pathogens. Particularly, AMPs were rationally designed to target the BamA and obtain novel antimicrobial peptide sequences. The designed AMPs were assessed for their antibacterial activities, mechanisms, and stability. Molecular docking and dynamics simulations demonstrated the interaction of both designed AMPs, 11pep and D-11pep, with the ß1, ß9, ß15, and ß16 chains of BamA, resulting in misfolding of outer membrane proteins and antibacterial effects. Subsequent antibacterial investigations confirmed the broad-spectrum activity of both 11pep and D-11pep, with D-11pep demonstrating higher potency against resistant Gram-negative bacteria. D-11pep exhibited MICs of 16, 8, and 32 µg/mL against carbapenem-resistant Escherichia coli, carbapenem-resistant Pseudomonas aeruginosa, and multi-drug-resistant Acinetobacter baumannii, respectively, with a concomitant lower resistance induction. Mechanism of action studies confirmed that peptides could disrupt the bacterial outer membrane, aligning with the findings of molecular dynamics simulations. Additionally, D-11pep demonstrated superior stability and reduced toxicity in comparison to 11pep. The findings of this study underscore the efficacy of rational AMP design that targets BamA, along with the utilization of D-amino acid replacements as a strategy for developing AMPs against drug-resistant bacteria.

Synthesis of tryptophan-dehydrobutyrine diketopiperazine and biological activity of hangtaimycin and its co-metabolites.

An improved synthesis for tryptophan-dehydrobutyrine diketopiperazine (TDD), a co-metabolite of the hybrid polyketide/non-ribosomal peptide hangtaimycin, starting from ʟ-tryptophan is presented. Comparison to TDD isolated from the hangtaimycin producer Streptomyces spectabilis confirmed its S configuration. The X-ray structure of the racemate shows an interesting dimerisation through hydrogen bridges. The results from bioactivity testings of hangtaimycin, TDD and the hangtaimycin degradation product HTM222 are given.

The Mechanism of Dehydrating Bimodules in trans-Acyltransferase Polyketide Biosynthesis: A Showcase Study on Hepatoprotective Hangtaimycin.

A bioassay-guided fractionation led to the isolation of hangtaimycin (HTM) from Streptomyces spectabilis CCTCC M2017417 and the discovery of its hepatoprotective properties. Structure elucidation by NMR suggested the need for a structural revision. A putative HTM degradation product was also isolated and its structure was confirmed by total synthesis. The biosynthetic gene cluster was identified and resembles a hybrid trans-AT PKS/NRPS biosynthetic machinery whose first PKS enzyme contains an internal dehydrating bimodule, which is usually found split in other trans-AT PKSs. The mechanisms of such dehydrating bimodules have often been proposed, but have never been deeply investigated. Here we present in vivo mutations and in vitro enzymatic experiments that give first and detailed mechanistic insights into catalysis by dehydrating bimodules.

Natural Hydroxamate-Containing Siderophore Acremonpeptides A-D and an Aluminum Complex of Acremonpeptide D from the Marine-Derived Acremonium persicinum SCSIO 115.

Four new hydroxamate-containing natural product cyclopeptides designated acremonpeptides A-D (1-4), together with Al(III)-acremonpeptide D (5) were obtained from the marine fungus Acremonium persicinum SCSIO 115. The planar structures of 1-5 were established on the basis of HRMS as well as 1D and 2D NMR data sets. Moreover, the amino acid absolute configurations were determined using Marfey's method. Compounds 1-5 all feature three 2-amino-5-(N-hydroxyacetamido)pentanoic acid (N5-hydroxy-N5-acetyl-l-ornithine) metal ion chelating moieties. Beyond their discovery and structure elucidation, in vitro bioassays revealed acremonpeptides A (1), B (2), and Al(III)-acremonpeptide D (5) as moderate antiviral agents for herpes simplex virus 1 with EC50 values of 16, 8.7, and 14 µM, respectively.

Specific cancer stem cell-therapy by albumin nanoparticles functionalized with CD44-mediated targeting.

BACKGROUND: Cancer stem cells (CSCs) are highly proliferative and tumorigenic, which contributes to chemotherapy resistance and tumor occurrence. CSCs specific therapy may achieve excellent therapeutic effects, especially to the drug-resistant tumors. RESULTS: In this study, we developed a kind of targeting nanoparticle system based on cationic albumin functionalized with hyaluronic acid (HA) to target the CD44 overexpressed CSCs. All-trans-retinoic acid (ATRA) was encapsulated in the nanoparticles with ultrahigh encapsulation efficiency (EE%) of 93% and loading content of 8.37%. TEM analysis showed the nanoparticles were spherical, uniform-sized and surrounded by a coating layer consists of HA. Four weeks of continuously measurements of size, PDI and EE% revealed the high stability of nanoparticles. Thanks to HA conjugation on the surface, the resultant nanoparticles (HA-eNPs) demonstrated high affinity and specific binding to CD44-enriched B16F10 cells. In vivo imaging revealed that HA-eNPs can targeted accumulate in tumor-bearing lung of mouse. The cytotoxicity tests illustrated that ATRA-laden HA-eNPs possessed better killing ability to B16F10 cells than free drug or normal nanoparticles in the same dose, indicating its good targeting property. Moreover, HA-eNPs/ATRA treatment decreased side population of B16F10 cells significantly in vitro. Finally, tumor growth was significantly inhibited by HA-eNPs/ATRA in lung metastasis tumor mice. CONCLUSIONS: These results demonstrate that the HA functionalized albumin nanoparticles is an efficient system for targeted delivery of antitumor drugs to eliminate the CSCs.

Amino Acid Conjugated Anthraquinones from the Marine-Derived Fungus Penicillium sp. SCSIO sof101.

Emodacidamides A-H (1-8), natural products featuring anthraquinone-amino acid conjugates, have been isolated from a marine-derived fungus, Penicillium sp. SCSIO sof101, together with known anthraquinones 9 and 10. The planar structures of 1-8 were elucidated using a combination of NMR spectroscopy and mass spectrometry. The absolute configurations of the amino acid residues were confirmed using Marfey's method and chiral-phase HPLC analyses. Additionally, isolates were evaluated for possible immunomodulatory and cytotoxic activities. Emodacidamides A (1), C (3), D (4), and E (5) inhibited interleukin-2 secretion from Jurkat cells with IC50 values of 4.1, 5.1, 12, and 5.4 µM, respectively.

Discovery of olimycin E from Streptomyces sp. 11695.

A new natural product olimycin E (1), together with two known compounds of divergolide R (2) and olimycin B (3), were obtained from the marine-derived Streptomyces sp. 11695. The structures of 1-3 were established on the basis of HRESIMS as well as 1D and 2D NMR datasets. The absolute configuration of 1 is identified as 4 R, 6S, 7S, 10 R by comparison the experiment ECD with that of the theoretical ECD. Antibacterial results showed that compound 2 have antibacterial activities against Staphylococcus aureus and MRSA with the MIC values of 32 µg/mL, respectively.

Methylation in hangtaimycin biosynthesis and its antibacterial activities.

About two-thirds of small molecule drugs contain methyl group and it plays a very important role in the drug development. So, methyltransferases catalyzing the methylation have always attracted great attention. Hangtaimycin (HTM) is a potent hepatoprotective agent. Previous study showed that its biosynthetic gene cluster contained three methyltransferase domains, but their characteristics in HTM biosynthetic pathway has not been revealed. In this study, we clarified multi-methylations in HTM biosynthesis in vivo. It showed that the two S-adenosylmethionine-dependent methyltransferases (SAM-MTs) of HtmA2(-module 6)-MT domain and HtmB2(-module 18)-MT domain are responsible for the installation of methyl group at C-45 and N-12, respectively, whereas the FK506 methyltransferase (FKMT) type O-methyltransferase of HtmB1(-module 16)-MT domain take care of the methylation at O-21 of HTM. We also reported the antibacterial activities of HTM in this study, and found that it showed activities against M. luteus, B. thuringiensis and A. baumannii with MIC of 4 µg/mL, 4 µg/mL, and 64 µg/mL, respectively.

Virtual screening and biological activity evaluation of novel efflux pump inhibitors targeting AdeB.

The AdeABC efflux pump is an important mechanism causing multidrug resistance in Acinetobacter baumannii, and its main component AdeB can recognize carbapenems, aminoglycosides, and other multi-class antibiotics and efflux them intracellularly, which is an ideal target for the development of anti-multidrug resistant bacteria drugs. Here, we combined multiple computer-aided drug design methods to target AdeB to identify promising novel structural inhibitors. Virtual screening was performed by molecular docking and molecular dynamics simulation (MD) and 12 potential compounds were identified from the databases. Meanwhile, their biological activities were validated by in vitro activity assays, and ChemDiv L676-2179 (γ-IFN), ChemDiv L676-1461, and Chembridge 53717615 were confirmed to suppress efflux effects and restore antibiotic susceptibility of resistant bacteria, which are expected to be developed as adjuvant drugs for the treatment of multi-drug resistant Acinetobacter baumannii clinical infections.

Discovery and engineered overproduction of antimicrobial nucleoside antibiotic A201A from the deep-sea marine actinomycete Marinactinospora thermotolerans SCSIO 00652.

Marinactinospora thermotolerans SCSIO 00652, originating from a deep-sea marine sediment of the South China Sea, was discovered to produce antimicrobial nucleoside antibiotic A201A. Whole-genome scanning and annotation strategies enabled us to localize the genes responsible for A201A biosynthesis and to experimentally identify the gene cluster; inactivation of mtdF, an oxidoreductase gene within the suspected gene cluster, abolished A201A production. Bioinformatics analysis revealed that a gene designated mtdA furthest upstream within the A201A biosynthetic gene cluster encodes a GntR family transcriptional regulator. To determine the role of MtdA in regulating A201A production, the mtdA gene was inactivated in frame and the resulting ΔmtdA mutant was fermented alongside the wild-type strain as a control. High-performance liquid chromatography (HPLC) analyses of fermentation extracts revealed that the ΔmtdA mutant produced A201A in a yield ∼25-fold superior to that of the wild-type strain, thereby demonstrating that MtdA is a negative transcriptional regulator governing A201A biosynthesis. By virtue of its high production capacity, the ΔmtdA mutant constitutes an ideal host for the efficient large-scale production of A201A. These results validate M. thermotolerans as an emerging source of antibacterial agents and highlight the efficiency of metabolic engineering for antibiotic titer improvement.

Halogenated anthraquinones from the marine-derived fungus Aspergillus sp. SCSIO F063.

Metabolomic investigations focusing on the marine-derived fungus Aspergillus sp. SCSIO F063 have unveiled seven new chlorinated anthraquinones (1-7) related to averantin, together with five known analogues (11-15) when the fungus was fermented using sea salt-containing potato dextrose broth. Through the addition of sodium bromide to the broth, two new brominated anthraquinones (8, 9) and one new nonhalogenated anthraquinone (10) were obtained from the fungal mycelia. Their structures were elucidated by extensive spectroscopic analyses including MS and 1D and 2D NMR data. One metabolite, 6-O-methyl-7-chloroaveratin (2), displayed inhibition activity against three human tumor cell lines, SF-268, MCF-7, and NCI-H460, with IC(50) values of 7.11, 6.64, and 7.42 µM, respectively.

Effects of arctiin on streptozotocin-induced diabetic retinopathy in Sprague-Dawley rats.

Diabetic retinopathy is one of the most common and severe complications of diabetes mellitus. Arctiin, a bioactive compound isolated from the dry seeds of Arctium lappa L., has been reported to have antidiabetic activity. In this study, we investigated the effect of arctiin on the serum glucose and HBA1c levels, the blood viscosity, and VEGF expression in the retinal tissues of rats with diabetic retinopathy. We first extracted arctiin from Fructus Arctii and then investigated its chemopreventive effect on streptozotocin-induced diabetic retinopathy in male Sprague-Dawley rats. After the induction of diabetes using streptozotocin (30 mg/kg, i. p.), the rats were randomly divided into five groups (n = 20 per group) and treated with intragastric doses of 30, 90, or 270 mg/kg/d wt of arctiin, 100 mg/kg/d wt of calcium dobesilate, or 0.5 % CMC-Na. Twenty nondiabetic sham-treated rats were treated with 0.5 % CMC-Na. The occurrence of diabetic retinopathy did not differ dramatically among the groups. However, at week 16, the glycosylated haemoglobin (HBA1c) level was significantly decreased in all of the arctiin-treated groups when compared with the control group, and the serum glucose level was also decreased in the rats treated with the highest dose of arctiin. In addition, treatment with arctiin ameliorated retinal oedema, detachment of the retina, and VEGF expression in the retina, as detected using histological and immunochemical examinations. Finally, arctiin increased the viability of retinal microvascular endothelial cells in vitro. Together, these findings demonstrate that arctiin decreases the severity of diabetic complications, demonstrating the importance of this compound as an inhibitor of diabetic retinopathy.

Two new streptovaricin derivatives from mutants of Streptomyces spectabilis CCTCC M2017417.

Two new ansamycin derivatives, damavaricin H (1) and protostreptovaricin VI (2) were isolated from the Streptomyces spectabilis CCTCC M2017417 derived mutants of ΔstvP5 and ΔstvA2, respectively. The structures of 1 and 2 were established by analysis of the HRESIMS as well as 1D and 2D NMR datasets. The minimum inhibitory concentration (MIC) results showed that compounds 1 and 2 possessed the corresponding anti-MRSA bioactivities of 4 ∼ 8 µg/ml and 8 ∼ 16 µg/ml, which confirmed the structure-activity relationships of streptovaricins reported previously and also revealed that addition of the hydroxyl group at C-8 increased the anti-MRSA activity.

Subtly manipulating Zn2+-coordinated configurations with a complexing agent to boost the reversibility of the zinc anode.

By using ethylenediamine (En) as a complexing agent, the impact of various Zn2+ coordinated configurations on Zn anode reversibility was systematically studied. With the predominant configurations of [Zn(En)]2+ and [Zn(En)2]2+ in the electrolyte, both symmetric Zn/Zn cells and Zn/NiHCF full cells exhibit significantly improved cycling stability compared to the counterparts with pure ZnSO4 electrolyte.

Antibacterial natural products lobophorin L and M from the marine-derived Streptomyces sp. 4506.

Two new spirotetronate natural products, lobophorin L (1) and lobophorin M (2), together with three known lobophorin-like spirotetronate antibiotics (3-5) and two known ansamycins (6-7), were isolated from the marine-derived Streptomyces sp. 4506. The structures of 1 and 2 were established on the basis of HRESIMS as well as 1D and 2D NMR datasets. Antibacterial assay showed that, compounds 1 and 3-5 exhibited strong to moderate antibacterial activities against Micrococcus luteus and Bacillus thuringiensis with MIC values ranging from 0.0625 to 8 µg/mL, while compounds 3 and 6 showed weak antibacterial activities against Staphylococcus aureus and MRSA. The antibacterial activities of the lobophorins in this study indicated that the more substitution number of the sugar moieties at C-9 of the lobophorin, the stronger antimicrobial properties it may deserve, and the higher the oxidation degree of substituent group at C-3D, the better antibacterial activities of its corresponding compound could be.

A mycophenolic acid derivative from the fungus Penicillium sp. SCSIO sof101.

Mycophenolic acid (MPA) is a group of metabolite derived from several species of Penicillium, which shows potent bioactivity. In this study, a new derivative of MPA compound named penicacid D (1), was isolated from the marine derived fungus Penicillium sp. SCSIO sof101, along with seven known compounds (2-8). Their structures were elucidated based on the HR-ESI-MS and NMR data. Moreover, the 1H and 13C NMR data of compound 2 and the 13C NMR data of compound 3 are reported. Compounds 1, 4 and 6 exhibited weak activities against Escherichia coli (clinical isolation number 100385570) and Acinetobacter baumannii (clinical isolation number 100069).

Uncovering the cytochrome P450-catalyzed methylenedioxy bridge formation in streptovaricins biosynthesis.

Streptovaricin C is a naphthalenic ansamycin antibiotic structurally similar to rifamycins with potential anti-MRSA bioactivities. However, the formation mechanism of the most fascinating and bioactivity-related methylenedioxy bridge (MDB) moiety in streptovaricins is unclear. Based on genetic and biochemical evidences, we herein clarify that the P450 enzyme StvP2 catalyzes the MDB formation in streptovaricins, with an atypical substrate inhibition kinetics. Furthermore, X-ray crystal structures in complex with substrate and structure-based mutagenesis reveal the intrinsic details of the enzymatic reaction. The mechanism of MDB formation is proposed to be an intramolecular nucleophilic substitution resulting from the hydroxylation by the heme core and the keto-enol tautomerization via a crucial catalytic triad (Asp89-His92-Arg72) in StvP2. In addition, in vitro reconstitution uncovers that C6-O-methylation and C4-O-acetylation of streptovaricins are necessary prerequisites for the MDB formation. This work provides insight for the MDB formation and adds evidence in support of the functional versatility of P450 enzymes.

Sol-Gel Synthesis and in Situ X-ray Diffraction Study of Li3Nd3W2O12 as a Lithium Container.

In this work, garnet-framework Li3Nd3W2O12 as a novel insertion-type anode material has been prepared via a facile sol-gel method and examined as a lithium container for lithium ion batteries (LIBs). Li3Nd3W2O12 shows a charge capacity of 225 mA h g-1 at 50 mA g-1, and with the current density increasing up to 500 mA g-1, the charge capacity can still be maintained at 186 mA h g-1. After cycling at 500 mA g-1 for 500 cycles, Li3Nd3W2O12 retains about 85% of its first charge capacity changed from 190.2 to 161 mA h g-1. Furthermore, in situ X-ray diffraction technique is adopted for the understanding of the insertion/extraction mechanism of Li3Nd3W2O12. The full-cell configuration LiFePO4/Li3Nd3W2O12 is also assembled to evaluate the potential of Li3Nd3W2O12 for practical application. These results show that Li3Nd3W2O12 is such a promising anode material for LIBs with excellent electrochemical performance and stable structure.

Circulating Tumor Cells: From Theory to Nanotechnology-Based Detection.

Cancer stem cells with stem-cell properties are regarded as tumor initiating cells. Sharing stem-cell properties, circulating tumor cells (CTCs) are responsible for the development of metastasis, which significant affects CTC analysis in clinical practice. Due to their extremely low occurrence in blood, however, it is challenging to enumerate and analyze CTCs. Nanotechnology is able to address the problems of insufficient capture efficiency and low purity of CTCs owing to the unique structural and functional properties of nanomaterials, showing strong promise for CTC isolation and detection. In this review, we discuss the role of stem-like CTCs in metastases, provide insight into recent progress in CTC isolation and detection approaches using various nanoplatforms, and highlight the role of nanotechnology in the advancement of CTC research.

Cytochalasan and Tyrosine-Derived Alkaloids from the Marine Sediment-Derived Fungus Westerdykella dispersa and Their Bioactivities.

Six new cytochalasans, designated as 18-oxo-19,20-dihydrophomacin C (1), 18-oxo-19-methoxy-19,20- dihydrophomacin C (2), 18-oxo-19-hydroxyl-19,20-dihydrophomacin C (3), 19,20-dihydrophomacin C (4), 19-methoxy-19,20-dihydrophomacin C (5), 19-hydroxyl-19,20-dihydrophomacin C (6), and one new tyrosine-derived alkaloid named as gymnastatin Z (8), together with two known compounds, phomacin B (7) and triticone D (9), were isolated from a solid-substrate fermentation culture of Westerdykella dispersa which was derived from marine sediments. Their structures were established on the basis of spectroscopic analysis using 1D and 2D NMR techniques, and comparison of NMR data to those of known compounds. The anti-bacterial and cytotoxic activities assays of all isolated compounds were evaluated against eight human pathogenic bacteria and five human cancer cell lines, respectively. Compound 8 exhibited moderate activity against B. subtilis with MIC values of 12.5 µg/mL, while compounds 5, 7 and 8 displayed moderate inhibitory activities against five human cancer cell lines (MCF-7, HepG2, A549, HT-29 and SGC-7901), with IC50 values ranging from 25.6 to 83.7 µM.