ABSTRACT
Mutations in a Plasmodium de-ubiquitinase UBP1 have been linked to antimalarial drug resistance. However, the UBP1-mediated drug-resistant mechanism remains unknown. Through drug selection, genetic mapping, allelic exchange, and functional characterization, here we show that simultaneous mutations of two amino acids (I1560N and P2874T) in the Plasmodium yoelii UBP1 can mediate high-level resistance to mefloquine, lumefantrine, and piperaquine. Mechanistically, the double mutations are shown to impair UBP1 cytoplasmic aggregation and de-ubiquitinating activity, leading to increased ubiquitination levels and altered protein localization, from the parasite digestive vacuole to the plasma membrane, of the P. yoelii multidrug resistance transporter 1 (MDR1). The MDR1 on the plasma membrane enhances the efflux of substrates/drugs out of the parasite cytoplasm to confer multidrug resistance, which can be reversed by inhibition of MDR1 transport. This study reveals a previously unknown drug-resistant mechanism mediated by UBP1 through altered MDR1 localization and substrate transport direction in a mouse model, providing a new malaria treatment strategy.
Subject(s)
Antimalarials , Endopeptidases , Malaria, Falciparum , Plasmodium yoelii , Animals , Mice , Plasmodium yoelii/genetics , Malaria, Falciparum/parasitology , Plasmodium falciparum/genetics , Antimalarials/therapeutic use , Drug Resistance, Multiple/genetics , Drug Resistance/geneticsABSTRACT
The step- and atom-efficient dimerization strategy is frequently used in nature to build structural complexity and diversity. We propose the rationale and structural features of the versatile monomers that are responsible for "diversity through dimerization". Using 5-FAM-maleimide combined with a UHPLC-MS/MS-FBMN workflow, we successfully identified a diverse set of dimeric natural products from fungus Panus rudis F01315, in which all four complex 4'5-ring scaffolds are derived from one monomeric epoxyquinol and endowed with functional diversity.
Subject(s)
Biological Products , Tandem Mass Spectrometry , Biological Products/chemistry , Dimerization , FungiABSTRACT
There is an urgent need to discover new antibacterial drugs and provide new treatment options for clinical antimicrobial resistance (AMR) pathogen infections. Inspired by the structural insights from analyzing the co-crystal structure of lefamulin with the ribosomes of S. aureus, a series of novel pleuromutilin derivatives of phenylene sulfide incorporated with urea moiety were designed and synthesized. The structure-activity relationship (SAR) study revealed that derivatives with urea in the meta position of phenylene sulfide had optimal antibacterial activities in vitro. Among them, 21h was the most potent one against Methicillin-resistant Staphylococcus aureus (MRSA) and clinical AMR Gram-positive bacteria with minimum inhibitory concentrations (MICs) in the range of 0.00195-0.250 µg/mL. And it possessed low resistance frequency, prolonged Post-Antibiotic Effect and the capability to overcome lefamulin-induced resistance. Furthermore, 21h exhibited potent antibacterial activity in vivo in both the thigh infection model and trauma infection model, representing a promising lead for the development of new antibiotics against Gram-positive pathogens, especially for AMR bacteria.
Subject(s)
Anti-Bacterial Agents , Methicillin-Resistant Staphylococcus aureus , Anti-Bacterial Agents/pharmacology , Anti-Bacterial Agents/chemistry , Staphylococcus aureus , Structure-Activity Relationship , Microbial Sensitivity Tests , Sulfides/pharmacology , PleuromutilinsABSTRACT
Multidrug resistance (MDR) in cancer remains a major challenge for the success of chemotherapy. Natural products have been a rich source for the discovery of drugs against MDR cancers. Here, we applied high-throughput cytotoxicity screening of an in-house natural product library against MDR SGC7901/VCR cells and identified that the cyclodepsipeptide verucopeptin demonstrated notable antitumor potency. Cytological profiling combined with click chemistry-based proteomics revealed that ATP6V1G directly interacted with verucopeptin. ATP6V1G, a subunit of the vacuolar H+-ATPase (v-ATPase) that has not been previously targeted, was essential for SGC7901/VCR cell growth. Verucopeptin exhibited strong inhibition of both v-ATPase activity and mTORC1 signaling, leading to substantial pharmacological efficacy against SGC7901/VCR cell proliferation and tumor growth in vivo. Our results demonstrate that targeting v-ATPase via its V1G subunit constitutes a unique approach for modulating v-ATPase and mTORC1 signaling with great potential for the development of therapeutics against MDR cancers.
Subject(s)
Antineoplastic Agents/pharmacology , Biological Products/pharmacology , Depsipeptides/pharmacology , Drug Resistance, Multiple/drug effects , Drug Resistance, Neoplasm/drug effects , Vacuolar Proton-Translocating ATPases/antagonists & inhibitors , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Biological Products/chemical synthesis , Biological Products/chemistry , Cell Line, Tumor , Cell Proliferation/drug effects , Cell Survival/drug effects , Cells, Cultured , Depsipeptides/chemical synthesis , Depsipeptides/chemistry , Drug Screening Assays, Antitumor , Female , Humans , Male , Mechanistic Target of Rapamycin Complex 1/antagonists & inhibitors , Mechanistic Target of Rapamycin Complex 1/metabolism , Mice , Mice, Inbred BALB C , Mice, Nude , Neoplasms, Experimental/drug therapy , Neoplasms, Experimental/metabolism , Neoplasms, Experimental/pathology , Protein Subunits/drug effects , Proteomics , Vacuolar Proton-Translocating ATPases/metabolismABSTRACT
A synthesis program for structurally complex macrocycles is very challenging. Herein, we propose a biosynthesis pathway of the pyranylated cyclodepsipeptide verucopeptin to make enough supply and to diversify verucopeptin by genetic manipulation and one-step semisynthesis. The synthesis relies on the intrinsic reactivity of the interchangeable hemiketal pyrane and opened keto along with adjacent alkene. Biological evaluation of verucopeptin-oriented analogs delivers a potent AMP-activated protein kinase (AMPK) agonist, antibacterial agent, and selective NFκB modulator.
Subject(s)
AMP-Activated Protein Kinases/metabolism , Anti-Bacterial Agents/pharmacology , Depsipeptides/pharmacology , NF-kappa B/antagonists & inhibitors , Protein Kinase Inhibitors/pharmacology , Staphylococcus aureus/drug effects , Actinomadura/chemistry , Anti-Bacterial Agents/biosynthesis , Anti-Bacterial Agents/chemistry , Depsipeptides/biosynthesis , Depsipeptides/chemistry , HEK293 Cells , Humans , Microbial Sensitivity Tests , Molecular Structure , NF-kappa B/metabolism , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/metabolism , Signal Transduction/drug effectsABSTRACT
Four new 12,8-Eudesmanolides (1-4) and one known compound 5 named 13-Hydroxy-3,7(11)-eudesmadien-12,8-olide, were isolated from a mangrove rhizosphere-derived fungus Eutypella sp. 1-15. Their structures with absolute stereochemistry were determined by the comprehensive spectroscopic data, experimental and calculated ECD analysis. Compound 1 exhibited potent anticancer activity against JEKO-1 and HepG2 with IC50 values of 8.4 and 28.5 µM, respectively. Additionally, compound 1 also showed moderate antimicrobial activity.
Subject(s)
Antineoplastic Agents/isolation & purification , Antineoplastic Agents/pharmacology , Sesquiterpenes/isolation & purification , Sesquiterpenes/pharmacology , Xylariales/chemistry , Anti-Infective Agents/chemistry , Anti-Infective Agents/isolation & purification , Anti-Infective Agents/pharmacology , Antineoplastic Agents/chemistry , Cell Line, Tumor , Humans , Inhibitory Concentration 50 , Rhizosphere , Sesquiterpenes/chemistry , Soil Microbiology , Spectrum Analysis , Xylariales/isolation & purificationABSTRACT
Thin bilayers of contrasting nanomaterials are ubiquitous in solution-processed electronic devices and have potential relevance to a number of applications in flexible electronics. Motivated by recent mesoscopic simulations demonstrating synergistic mechanical interactions between thin films of single-wall carbon nanotubes (SWCNTs) and spherical nanocrystal (NC) inclusions, we use a thin-film wrinkling approach to query the compressive mechanics of hybrid nanotube/nanocrystal coatings adhered to soft polymer substrates. Our results show an almost 2-fold enhancement in the Young modulus of a sufficiently thin SWCNT film associated with the presence of a thin interpenetrating overlayer of semiconductor NCs. Mesoscopic distinct-element method simulations further support the experimental findings by showing that the additional noncovalent interfaces introduced by nanocrystals enhance the modulus of the SWCNT network and hinder network wrinkling.
ABSTRACT
Ultrathin carbon nanotube films have gathered attention for flexible electronics applications. Unfortunately, their network structure changes significantly even under small applied strains. We perform mesoscopic distinct element method simulations and develop an atomic-scale picture of the network stress relaxation. On this basis, we put forward the concept of mesoscale design by the addition of excluded-volume interactions. We integrate silicon nanoparticles into our model and show that the nanoparticle-filled networks present superior stability and mechanical response relative to those of pure films. The approach opens new possibilities for tuning the network microstructure in a manner that is compatible with flexible electronics applications.
ABSTRACT
The geometry and internal packing of twisted ropes composed of carbon nanotubes (CNTs) are considered, and a numerical solution in the context of the mesoscopic distinct element method (MDEM) is proposed. Compared to the state of the art, MDEM accounts in a computationally tractable manner for both the deformation of the fiber and the distributed van der Waals cohesive energy between fibers. These features enable us to investigate the torsional response in a new regime where the twisted rope develops packing rearrangements and aspect-ratio-dependent geometric nonlinearities. MDEM emerges as a robust simulation method for studying twisted agglomerates comprising semiflexible nanofibers.
ABSTRACT
Aspertetranones A-D (1-4), four new highly oxygenated putative rearranged triketide-sesquiterpenoid meroterpenes, were isolated from the marine algal-associated fungus Aspergillus sp. ZL0-1b14. On the basis of a comprehensive spectroscopic analysis, the planar structures of aspertetranones were determined to possess an unusual skeleton in the terpenoid part. The relative and absolute configurations of the aspertetranones were assigned on the basis of NOESY analysis, X-ray crystallography, and circular dichroism spectroscopy. Compounds 1-4 were evaluated for anti-inflammatory activity in LPS-stimulated RAW264.7 macrophages. Aspertetranone D exhibited an inhibitory effect against IL-6 production with 69% inhibition at 40 µM.
Subject(s)
Aspergillus/chemistry , Sesquiterpenes/isolation & purification , Algorithms , Animals , Anti-Inflammatory Agents/pharmacology , China , Crystallography, X-Ray , Interleukin-6/antagonists & inhibitors , Lipopolysaccharides/pharmacology , Macrophages/drug effects , Marine Biology , Mice , Molecular Conformation , Molecular Structure , Nitric Oxide/analysis , Nuclear Magnetic Resonance, Biomolecular , Sesquiterpenes/chemistry , Sesquiterpenes/pharmacologyABSTRACT
Two new spirooxindole alkaloids spindomycins A (1) and B (2) were isolated from rhizosphere strain Streptomyces sp. xzqh-9. Their structures were elucidated by comprehensive spectroscopic analyses of NMR and MS data. The absolute configurations of 1 and 2 were determined by experimental and theoretical calculation of electronic circular dichroism (ECD). Antitumor, lactate dehydrogenase, and tyrosine kinase inhibitory activities of two compounds were evaluated, while only spindomycin B (2) exhibited weak inhibitory activity against tyrosine kinase Bcr-Abl.
Subject(s)
Indole Alkaloids/pharmacology , Indoles/chemistry , Rhizosphere , Spiro Compounds/chemistry , Streptomyces/chemistry , Antineoplastic Agents/pharmacology , Cell Proliferation/drug effects , Circular Dichroism , Fusion Proteins, bcr-abl/antagonists & inhibitors , Humans , Indole Alkaloids/chemistry , Indole Alkaloids/isolation & purification , Inhibitory Concentration 50 , L-Lactate Dehydrogenase/metabolism , Molecular Structure , Neoplasms/drug therapy , Neoplasms/pathology , Nuclear Magnetic Resonance, Biomolecular , Oxindoles , Protein Kinase Inhibitors/pharmacology , Spectrometry, Mass, Electrospray Ionization , Spiro Compounds/isolation & purification , Spiro Compounds/pharmacology , Tumor Cells, CulturedABSTRACT
We combine experiments and distinct element method simulations to understand the stability of rings and rackets formed by single-walled carbon nanotubes assembled into ropes. Bending remains a soft deformation mode in ropes because intra-rope sliding of the constituent nanotubes occurs with ease. Our simulations indicate that the formation of these aggregates can be attributed to the mesoscopic mechanics of entangled nanotubes and to the sliding at the contacts. Starting from the single-walled carbon nanotubes, the sizes of the rings and rackets' heads increase with the rope diameter, indicating that the stability of the experimental aggregates can be largely explained by the competition between bending and van der Waals adhesion energies. Our results and simulation method should be useful for understanding nanoscale fibers in general.
