An antibiotic preorganized for ribosomal binding overcomes antimicrobial resistance.

We report the design conception, chemical synthesis, and microbiological evaluation of the bridged macrobicyclic antibiotic cresomycin (CRM), which overcomes evolutionarily diverse forms of antimicrobial resistance that render modern antibiotics ineffective. CRM exhibits in vitro and in vivo efficacy against both Gram-positive and Gram-negative bacteria, including multidrug-resistant strains of Staphylococcus aureus, Escherichia coli, and Pseudomonas aeruginosa. We show that CRM is highly preorganized for ribosomal binding by determining its density functional theory-calculated, solution-state, solid-state, and (wild-type) ribosome-bound structures, which all align identically within the macrobicyclic subunits. Lastly, we report two additional x-ray crystal structures of CRM in complex with bacterial ribosomes separately modified by the ribosomal RNA methylases, chloramphenicol-florfenicol resistance (Cfr) and erythromycin-resistance ribosomal RNA methylase (Erm), revealing concessive adjustments by the target and antibiotic that permit CRM to maintain binding where other antibiotics fail.

Production of Bioactive Porcine Lactoferrin through a Novel Glucose-Inducible Expression System in Pichia pastoris: Unveiling Antimicrobial and Anticancer Functionalities.

Lactoferrin (LF) stands as one of the extensively investigated iron-binding glycoproteins within milk, exhibiting diverse biological functionalities. The global demand for LF has experienced consistent growth. Biotechnological strategies aimed at enhancing LF productivity through microbial expression systems offer substantial cost-effective advantages and exhibit fewer constraints compared to traditional animal bioreactor technologies. This study devised a novel recombinant plasmid, wherein the AOX1 promoter was replaced with a glucose-inducible G1 promoter (PG1) to govern the expression of recombinant porcine LF (rpLF) in Pichia pastoris GS115. High-copy-number PG1-rpLF yeast clones were meticulously selected, and subsequent induction with 0.05 g/L glucose demonstrated robust secretion of rpLF. Scaling up production transpired in a 5 L fermenter, yielding an estimated rpLF productivity of approximately 2.8 g/L by the conclusion of glycerol-fed fermentation. A three-step purification process involving tangential-flow ultrafiltration yielded approximately 6.55 g of rpLF crude (approximately 85% purity). Notably, exceptional purity of rpLF was achieved through sequential heparin and size-exclusion column purification. Comparatively, the present glucose-inducible system outperformed our previous methanol-induced system, which yielded a level of 87 mg/L of extracellular rpLF secretion. Furthermore, yeast-produced rpLF demonstrated affinity for ferric ions (Fe3+) and exhibited growth inhibition against various pathogenic microbes (E. coli, S. aureus, and C. albicans) and human cancer cells (A549, MDA-MB-231, and Hep3B), similar to commercial bovine LF (bLF). Intriguingly, the hydrolysate of rpLF (rpLFH) manifested heightened antimicrobial and anticancer effects compared to its intact form. In conclusion, this study presents an efficient glucose-inducible yeast expression system for large-scale production and purification of active rpLF protein with the potential for veterinary or medical applications.

Discovery of a structural class of antibiotics with explainable deep learning.

The discovery of novel structural classes of antibiotics is urgently needed to address the ongoing antibiotic resistance crisis1-9. Deep learning approaches have aided in exploring chemical spaces1,10-15; these typically use black box models and do not provide chemical insights. Here we reasoned that the chemical substructures associated with antibiotic activity learned by neural network models can be identified and used to predict structural classes of antibiotics. We tested this hypothesis by developing an explainable, substructure-based approach for the efficient, deep learning-guided exploration of chemical spaces. We determined the antibiotic activities and human cell cytotoxicity profiles of 39,312 compounds and applied ensembles of graph neural networks to predict antibiotic activity and cytotoxicity for 12,076,365 compounds. Using explainable graph algorithms, we identified substructure-based rationales for compounds with high predicted antibiotic activity and low predicted cytotoxicity. We empirically tested 283 compounds and found that compounds exhibiting antibiotic activity against Staphylococcus aureus were enriched in putative structural classes arising from rationales. Of these structural classes of compounds, one is selective against methicillin-resistant S. aureus (MRSA) and vancomycin-resistant enterococci, evades substantial resistance, and reduces bacterial titres in mouse models of MRSA skin and systemic thigh infection. Our approach enables the deep learning-guided discovery of structural classes of antibiotics and demonstrates that machine learning models in drug discovery can be explainable, providing insights into the chemical substructures that underlie selective antibiotic activity.

Tapping into Tapajos: antibacterial potential of fungal strains isolated from decaying wood in the Brazilian Amazon.

The emergence of bacterial resistance to antimicrobials poses a significant health threat. To address this issue, exploring the fungal diversity in freshwater environments in the Amazon Forest has potential in the search for new antimicrobials. This study aimed to investigate the production of antibacterial metabolites by aquatic fungi from Amazon lakes, specifically Lake Juá and Lake Maicá (Brazil-PA). The fungal isolates were obtained from wood fragments submerged in these lakes, and the ethyl acetate extracts were evaluated for antibacterial activity against Staphylococcus aureus ATCC 25923, S. aureus (MRSA), ATCC 43300, Escherichia coli ATCC 25922, and E. coli (ESBL) NCTC 13353. Additionally, toxicity of the extracts (EtOAc with antimicrobial activity) against human fibroblasts MRC-5 was investigated. The study identified 40 fungal strains with antimicrobial screening, and the ethyl acetate extracts of Fluviatispora C34, Helicascus C18, Monodictys C15, and Fusarium solani LM6281 exhibited antibacterial activity. F. solani LM6281 showed the lowest minimum inhibitory concentration (MIC) of 50 µg/mL against S. aureus strains and MIC of 100 µg/mL against E. coli strains including ESBL. The cytotoxicity (IC50) of the extract (EtOAc) of F. solani LM6281 was 34.5 µg/mL. Preliminary studies of the TLC culture and RNM-H from the extract (EtOAc) of F. solani suggested the presence of substances from the class of terpenes, quinones, phenolics, and flavonoids. This study highlights the potential of submerged wood fungi in the Amazon region to produce antibacterial substances, thus identifying them as sources of novel bioactive compounds with potential use in the pharmaceutical industry and regional bioeconomy.

Antimicrobial, Antibiofilm, and Anticancer Activities of Syzygium aromaticum Essential Oil Nanoemulsion.

In the current study, clove oil nanoemulsion (CL-nanoemulsion) and emulsion (CL-emulsion) were prepared through an ecofriendly method. The prepared CL-nanoemulsion and CL-emulsion were characterized using dynamic light scattering (DLS) and a transmission electron microscope (TEM), where results illustrated that CL-nanoemulsion droplets were approximately 32.67 nm in size and spherical in shape, while CL-nanoemulsion droplets were approximately 225.8 nm with a spherical shape. The antibacterial activity of CL-nanoemulsion and CL-emulsion was carried out using a microbroth dilution method. Results revealed that the preferred CL-nanoemulsion had minimal MIC values between 0.31 and 5 mg/mL. The antibiofilm efficacy of CL-nanoemulsion against S. aureus significantly decreased the development of biofilm compared with CL-emulsion. Furthermore, results illustrated that CL-nanoemulsion showed antifungal activity significantly higher than CL-emulsion. Moreover, the prepared CL-nanoemulsion exhibited outstanding antifungal efficiency toward Candida albicans, Cryptococcus neoformans, Aspergillus brasiliensis, A. flavus, and A. fumigatus where MICs were 12.5, 3.12, 0.78, 1.56, and 1.56 mg/mL, respectively. Additionally, the prepared CL-nanoemulsion was analyzed for its antineoplastic effects through a modified MTT assay for evaluating apoptotic and cytotoxic effects using HepG2 and MCF-7 cell lines. MCF-7 breast cancer cells showed the lowest IC50 values (3.4-fold) in CL-nanoemulsion relative to that of CL-emulsion. Thus, CL-nanoemulsion induces apoptosis in breast cancer cells by inducing caspase-8 and -9 activity and suppressing VEGFR-2. In conclusion, the prepared CL-nanoemulsion had antibacterial, antifungal, and antibiofilm as well as anticancer properties, which can be used in different biomedical applications after extensive studies in vivo.

Multifunctional nanofibrous mats: toward antibacterial and anti-inflammatory applications, and visual bacterial diagnosis.

In most circumstances, wounds face the challenges of bacterial invasions and inappropriate inflammatory responses when they lack proper wound management. Endowing dressings with both antibacterial and anti-inflammatory functions is a compelling strategy for resolving the above issues. However, seizing the right moment to change the dressings and providing satisfactory management of wounds are still urgently required. Herein, an antibacterial and anti-inflammatory nanofibrous mat is proposed by encapsulating antibiotic gentamicin sulfate (GS) and anti-inflammatory drug ibuprofen (IB) into nanofibers via a coaxial electrospinning technique and is further decorated with Prussian blue nanocrystals (PBNCs) to enhance anti-inflammatory activity and, more importantly, to monitor bacterial infections and guide dressing changes in a timely manner. Such a nanofibrous mat releases most of the therapeutic drugs within 120 min and reveals excellent antibacterial activity and anti-inflammatory ability. Specifically, it can destroy both Staphylococcus aureus (S. aureus) and Escherichia coli (E. coli), as well as conspicuously reduce the production of reactive oxygen species (ROS) and the expression of pro-inflammatory cytokines in macrophages. In addition, the nanofibrous mat can be used for point-of-use diagnosis of living bacteria relying on the naked eye or color analysis, which exhibits the potential of monitoring wound infection and guiding dressing changes promptly. This finding demonstrates the theranostic applications of multifunctional nanofibrous mats in wound healing.

DNA binding peptide CF-14 enhances bactericidal efficacy of eugenol/carvacrol nanoparticles to Escherichia coli.

To evaluate the bactericidal action of antimicrobial peptide CF-14, Eugenol (EU) and carvacrol (CAR) nanoparticles (NPs) less than 200 nm were surface-modified with CF14, gaining approximately 200 nm of EU-CF and CAR-CF NPs with swollen morphology. EU-CF and CAR-CF NPs were bactericidal to E. coli at dosage of 0.09% and 0.07% (v/v), respectively; while they were just bacteriostatic to Staphylococcus aureus at 0.10% and 0.08% (v/v). Spectral variations in bacterial carbohydrates (1185-900 cm-1), lipids (3000-2800 cm-1) and DNA (1500-1185 cm-1) were obvious as evident from Fourier transform infrared spectroscopy (FTIR). A higher percentage of membrane damaged (non-revivable) E. coli than S. aureus was found, which indicated electrostatic interactions between Gram-negative E. coli with cationic CF conjugated NPs leading to DNA disintegration. Interestingly, EU-CF and CAR-CF NPs inhibited E. coli growth in orange juice without impacting flavour compounds.

Flexible Curcumin-Loaded Zn-MOF Hydrogel for Long-Term Drug Release and Antibacterial Activities.

Management of chronic inflammation and wounds has always been a key issue in the pharmaceutical and healthcare sectors. Curcumin (CCM) is an active ingredient extracted from turmeric rhizomes with antioxidant, anti-inflammatory, and antibacterial activities, thus showing significant effectiveness toward wound healing. However, its shortcomings, such as poor water solubility, poor chemical stability, and fast metabolic rate, limit its bioavailability and long-term use. In this context, hydrogels appear to be a versatile matrix for carrying and stabilizing drugs due to their biomimetic structure, soft porous microarchitecture, and favorable biomechanical properties. The drug loading/releasing efficiencies can also be controlled via using highly crystalline and porous metal-organic frameworks (MOFs). Herein, a flexible hydrogel composed of a sodium alginate (SA) matrix and CCM-loaded MOFs was constructed for long-term drug release and antibacterial activity. The morphology and physicochemical properties of composite hydrogels were analyzed by scanning electron microscopy (SEM), Fourier transform infrared spectroscopy (FT-IR), X-ray diffraction (XRD), ultraviolet-visible spectroscopy (UV-Vis), Raman spectroscopy, and mechanical property tests. The results showed that the composite hydrogel was highly twistable and bendable to comply with human skin mechanically. The as-prepared hydrogel could capture efficient CCM for slow drug release and effectively kill bacteria. Therefore, such composite hydrogel is expected to provide a new management system for chronic wound dressings.

Transcriptional Response of vanB Operon in Staphylococcus aureus Against Vancomycin and Teicoplanin Stress.

Staphylococcus aureus is a global pathogen and is responsible for causing severe life-threatening infections. The current study was designed to investigate transcriptional expression of different core, regulatory, and accessory genes within vanB operon under differential exposure of vancomycin and teicoplanin. Four isolates selected for the study, were confirmed to harbour vanB gene in which three isolates showed MIC breakpoint above 16 µg/ml and one isolate above 8 µg/ml against vancomycin while teicoplanin showed higher MIC breakpoint as compared to vancomycin. Antibiotic susceptibility results showed that these isolates were susceptible towards imipenem and linezolid. Transcriptional expressional analysis of the core gene of vanB operon showed that expression of vanB is increased under vancomycin stress but is inversely proportional to increase in the concentration of the vancomycin while under teicoplanin stress the expression of vanB showed no significant pattern. Similar expressional pattern was found for vanH gene for both the glycopeptides. In case of vanX, expression was significantly increased at 1 µg/ml exposure of vancomycin, however, no pattern could be observed in case of teicoplanin stress. In case of regulatory gene, vanR, significant increase in expression was observed under vancomycin and teicoplanin stress of 1 µg/ml, however vanS, showed significant increase in the expression under 1 µg/ml of vancomycin. The accessory gene, vanY showed marginal increase in expression under both the antibiotic, while in case of vanW, the expressional pattern was found to be inversely proportional to the increasing antibiotic concentration.

Identification of inhibitors for Agr quorum sensing system of Staphylococcus aureus by machine learning, pharmacophore modeling, and molecular dynamics approaches.

CONTEXT: Staphylococcus aureus is a highly pathogenic organism that is the most common cause of postoperative complications as well as severe infections like bacteremia and infective endocarditis. By mediating the formation of biofilms and the expression of virulent genes, the quorum sensing (QS) mechanism is a major contributor to the development of these diseases. By hindering its QS network, an innovative approach to avoiding this bacterial infection is taken. Targeting the AgrA of the Agr system serves as beneficial in holding the top position in the QS system cascade. METHODS: Using known AgrA inhibitors, the machine learning algorithms (artificial neural network, naïve Bayes, random forest, and support vector machine) and pharmacophore model were developed. The potential lead compounds were screened against the Zinc and COCONUT databases using the best pharmacophore hypothesis. The hits were then subjected second screening process using the best machine learning model. The predicted active compounds were then reranked based on the docking score. The stability of AgrA-lead compounds was studied using molecular dynamics approaches, and an ADME profile was also carried out. Five lead compounds, namely, CNP02386963,4,5-trihydroxy-2-[({7,13,14-trihydroxy-3,10-dioxo-2,9-dioxatetracyclo[6.6.2.04,16.011,15]hexadeca-1(14),4,6,8(16),11(15),12-hexaen-6-yl}oxy)methyl]benzoic acid, CNP0129274 4-(dimethylamino)-1,5,6,10,12,12a-hexahydroxy-6-methyl-3,11-dioxo-3,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, CNP0242717 3-Hydroxyasebotin, CNP0361624 3,4,5-trihydroxy-6-[(2,4,5,6,7-pentahydroxy-1-oxooctan-3-yl)oxy]oxane-2-carboxylic acid, and CNP0285058 2-{[4,5-dihydroxy-6-(hydroxymethyl)-3-[(3,4,5-trihydroxy-6-methyloxan-2-yl)oxy]oxan-2-yl]oxy}-2-(4-hydroxyphenyl)acetonitrile were obtained using the two-step virtual screening process. The molecular dynamics study revealed that the CNP0238696 was found to be stable in the binding pocket of AgrA. ADME profiles show that this compound has two Lipinski violations and low bioavailability. Further studies should be performed to assess the anti-biofilm activity of the lead compound in vitro.

Monomer and Oligomer Transition of Zinc Phthalocyanine Is Key for Photobleaching in Photodynamic Therapy.

Photodynamic therapy (PDT) is recognized as a powerful method to inactivate cells. However, the photosensitizer (PS), a key component of PDT, has suffered from undesired photobleaching. Photobleaching reduces reactive oxygen species (ROS) yields, leading to the compromise of and even the loss of the photodynamic effect of the PS. Therefore, much effort has been devoted to minimizing photobleaching in order to ensure that there is no loss of photodynamic efficacy. Here, we report that a type of PS aggregate showed neither photobleaching nor photodynamic action. Upon direct contact with bacteria, the PS aggregate was found to fall apart into PS monomers and thus possessed photodynamic inactivation against bacteria. Interestingly, the disassembly of the bound PS aggregate in the presence of bacteria was intensified by illumination, generating more PS monomers and leading to an enhanced antibacterial photodynamic effect. This demonstrated that on a bacterial surface, the PS aggregate photo-inactivated bacteria via PS monomer during irradiation, where the photodynamic efficiency was retained without photobleaching. Further mechanistic studies showed that PS monomers disrupted bacterial membranes and affected the expression of genes related to cell wall synthesis, bacterial membrane integrity, and oxidative stress. The results obtained here are applicable to other types of PSs in PDT.

Impact on S. aureus and E. coli Membranes of Treatment with Chlorhexidine and Alcohol Solutions: Insights from Molecular Simulations and Nuclear Magnetic Resonance.

Membranes form the first line of defence of bacteria against potentially harmful molecules in the surrounding environment. Understanding the protective properties of these membranes represents an important step towards development of targeted anti-bacterial agents such as sanitizers. Use of propanol, isopropanol and chlorhexidine can significantly decrease the threat imposed by bacteria in the face of growing anti-bacterial resistance via mechanisms that include membrane disruption. Here we have employed molecular dynamics simulations and nuclear magnetic resonance to explore the impact of chlorhexidine and alcohol on the S. aureus cell membrane, as well as the E. coli inner and outer membranes. We identify how sanitizer components partition into these bacterial membranes, and show that chlorhexidine is instrumental in this process.

Neobavaisoflavone Inhibits Biofilm Formation and α-Toxin Activity of Staphylococcus aureus.

Neobavaisoflavone had antimicrobial activities against Gram-positive multidrug-resistant (MDR) bacteria, but the effect of neobavaisoflavone on the virulence and biofilm formation of S. aureus has not been explored. The present study aimed to investigate the possible inhibitory effect of neobavaisoflavone on the biofilm formation and α-toxin activity of S. aureus. Neobavaisoflavone presented strong inhibitory effect on the biofilm formation and α-toxin activity of both methicillin-sensitive S. aureus (MSSA) and methicillin-resistant S. aureus (MRSA) strains at 25 µM, but did not affect the growth of S. aureus planktonic cells. Genetic mutations were identified in four coding genes, including cell wall metabolism sensor histidine kinase walK, RNA polymerase sigma factor rpoD, tetR family transcriptional regulator, and a hypothetical protein. The mutation of WalK (K570E) protein was identified and verified in all the neobavaisoflavone-induced mutant S. aureus isolates. The ASN501, LYS504, ILE544 and GLY565 of WalK protein act as hydrogen acceptors to form four hydrogen bonds with neobavaisoflavone by molecular docking analysis, and TRY505 of WalK protein contact with neobavaisoflavone to form a pi-H bond. In conclusion, neobavaisoflavone had excellent inhibitory effect on the biofilm formation and α-toxin activity of S. aureus. The WalK protein might be a potential target of neobavaisoflavone against S. aureus.

Essential Oil Composition of Grindelia squarrosa from Southern Idaho.

Grindelia squarrosa is an arid lands herb that has been used in Native American traditional medicine, is a potential source of pharmacologically active compounds, and has been explored as a source of biofuel. The purpose of this work was to examine the essential oil composition of G. squarrosa from southern Idaho. Gas chromatographic methods revealed the essential oil of G. squarrosa var. serrulata to be rich in monoterpenoids, α-pinene (21.9%), limonene (17.1%), terpinolene (10.6%), and borneol (6.5%). The essential oil composition of G. squarrosa from Idaho is similar to that previously reported from specimens collected from Montana and confirms the volatile phytochemistry of plants growing in North America. The major essential oil components were screened for antimicrobial activity against respiratory and dermal pathogens. (-)-ß-Pinene showed strong antibacterial activity against Streptococcus pneumoniae (MIC 39.1 µg/mL) and (-)-borneol showed strong activity against Staphylococcus aureus (MIC 78.1 µg/mL).

Yttrium Oxide Nanoparticle-Loaded, Self-Assembled Peptide Gel with Antibacterial, Anti-Inflammatory, and Proangiogenic Properties for Wound Healing.

Chronic wounds are a major healthcare challenge owing to their complex healing mechanism and number of impediments to the healing process, like infections, unregulated inflammation, impaired cellular functions, poor angiogenesis, and enhanced protease activity. Current topical care strategies, such as surgical debridement, absorption of exudates, drug-loaded hydrogels for infection and inflammation management, and exogenous supply of growth factors for angiogenesis and cell proliferation, slow the progression of wounds and reduce patient suffering but suffer from low overall cure rates. Therefore, we have developed a proteolytically stable, multifunctional nanoparticle loaded-peptide gel with inherent anti-inflammatory, antibacterial, and pro-angiogenic properties to provide a favorable wound healing milieu by restoring impaired cellular functions. We have fabricated a self-assembled, lauric acid-peptide conjugate gel, LA-LLys-DPhe-LLys-NH2, loaded with yttrium oxide (Y2O3) nanoparticles (NLG). Gel formed a nanofibrous structure, and nanoparticles were passively entrapped within the network. The surface morphology, stability, viscoelastic, and self-healing characteristics of gels were characterized. It showed a high stability against degradation by proteolytic enzymes and highly potent antibacterial activities against E. coli and S. aureus due to the presence of positively charged side chains of lysine in the peptide chain. It also exhibited an excellent antioxidant activity as well as ability to stimulate cell proliferation in murine fibroblast (L929) cells and human umbilical vein endothelial cells (HUVECs). The incorporation of nanoparticles promoted angiogenesis by upregulating pro-angiogenic genes, vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF2), and epidermal growth factor (EGFR), and the gel caused complete wound closure in cells. In summary, the Y2O3 nanoparticle-loaded lauric acid-peptide conjugate gel is able to elicit the desired tissue regeneration responses and, therefore, has a strong potential as a matrix for the treatment of chronic wounds.

Expression, purification and investigation of antibacterial activity of a novel hybrid peptide LL37/hBD-129 by applied comprehensive computational and experimental approaches.

Antibiotic-resistant pathogens have become a great universal health concern. Antimicrobial peptides (AMPs) are small amphipathic and cationic polypeptides with high therapeutic potential against various microorganisms containing drug-resistant strains. Two major groups of these peptides, which have antibacterial activity against Gram-positive and Gram-negative bacteria, antiviral activity, and even antifungal activity, are defensins and cathelicidins. Hybridization of various AMPs is an appropriate approach to achieving new fusion AMPs with high antibacterial activity but low cellular toxicity. In the current research, the amino-acid sequence of human cathelicidin LL-37 (2-31) and Human beta-defensin (hBD)-129 were combined, and the fusion protein was evaluated by bioinformatics tool. The designed AMP gene sequence was commercially synthesized and cloned in the pET-28a expression vector. The LL-37/hBD-129 fusion protein was expressed in E.coli BL21-gold (DE3). The expression of the recombinant protein was evaluated using the SDS-PAGE method. The LL37/hBD-129 was successfully expressed as a recombinant hybrid AMP in E.coli BL21-gold (DE3) strain. Purification of the expressed AMP was performed by Ni-NTA column affinity chromatography, and the purified AMP was validated using the Western blot technic. Finally, the antimicrobial activity of the fusion AMP against Staphylococcus aureus and Escherichia coli bacteria was assessed. Based on the in silico analysis and experimental evaluations, the fusion AMP showed a significant antimicrobial effect on E. coli and Staphylococcus aureus bacteria.

Effect of Axial Ligand Length on Biological and Anticancer Properties of Axially Disubstituted Silicon Phthalocyanines.

In this study, three new axially disubstituted silicon phthalocyanines (SiPc1-3) and their quaternized phthalocyanine derivatives (QSiPc1-3) were prepared and characterized. The biological properties (antioxidant, antimicrobial, antibiofilm, and microbial cell viability activities) of the water-soluble silicon phthalocyanines were examined, as well. A 1 % DMSO diluted with pure water was used as a solvent in biological activity studies. All the compounds exhibited high antioxidant activity. They displayed efficient antimicrobial and antimicrobial photodynamic therapeutic properties against various microorganisms, especially Gram (+) bacteria. Additionally, they demonstrated high antibiofilm activities against S. aureus and P. aeruginosa. In addition, 100 % bacterial reduction was obtained for all the studied phthalocyanines against E. coli viable cells. Besides, the DNA cleavage and binding features of compounds (QSiPc1-3) were studied using pBR322 DNA and CT-DNA, respectively. Furthermore, the human topoisomerase I enzyme inhibition activities of compounds QSiPc1-3 were studied. Anticancer properties of the water-soluble compounds were investigated using cell proliferation MTT assay. They exhibited anticarcinogenic activity against the human colon cancer cell line (DLD-1). Compounds QSiPc1 and QSiPc3 displayed a high anticarcinogenic effect on the DLD-1 cell line. The obtained results indicated that all the studied compounds may be effective biological agents and anticancer drugs after further investigations.

Syntheses and Antibacterial Evaluation of New Penicillium Metabolites Gregatins G and Thiocarboxylics C.

Two pairs of side-chain epimeric 3-methoxycarbonyl-dihydrofuran-4-ones with structures purported for thiocarboxylics C1/2 and gregatins G1/2 , isolated from Penicillium sp. Sb62, were synthesised for the first time in five steps and 17-25 % yield. Key steps were a Suzuki cross-coupling, a Yamaguchi esterification, and a base-induced Knoevenagel-type condensation. The optimum protecting group for the 10-OH group in the dienyl side-chain, orthogonal to necessary protecting groups on O-10 of the furanone, was found to be t-butyldiphenylsilyl (TBDPS). The specific rotations of our synthetic products deviated markedly from those reported for the natural isolates. In contrast to the isolates, the synthetic products were not active against Escherichia coli and Staphylococcus aureus bacteria.

Abundant tannic acid modified gelatin/sodium alginate biocomposite hydrogels with high toughness, antifreezing, antioxidant and antibacterial properties.

The acidity of high tannic acid (TA) content solution can destroy the structure of protein, such as gelatin (G). This causes a big challenge to introduce abundant TA into the G-based hydrogels. Here, the G-based hydrogel system with abundant TA as hydrogen bonds provider was constructed by a "protective film" strategy. The protective film around the composite hydrogel was first formed by the chelation of sodium alginate (SA) and Ca2+. Subsequently, abundant TA and Ca2+ were successively introduced into the hydrogel system by immersing method. This strategy effectively protected the structure of the designed hydrogel. After treatment with 0.3 w/v TA and 0.06 w/v Ca2+ solutions, the tensile modulus, elongation at break and toughness of G/SA hydrogel increased about 4-, 2-, and 6-fold, respectively. Besides, G/SA-TA/Ca2+ hydrogels exhibited good water retention, anti-freezing, antioxidant, antibacterial properties and low hemolysis ratio. Cell experiments showed that G/SA-TA/Ca2+ hydrogels possessed good biocompatibility and could promote cell migration. Therefore, G/SA-TA/Ca2+ hydrogels are expected to be used in the field of biomedical engineering. The strategy proposed in this work also provides a new idea for improving the properties of other protein-based hydrogels.

Quantifiable Relationship Between Antibacterial Efficacy and Electro-Mechanical Intervention on Nanowire Arrays.

Physical disruption is an important antibacterial means as it is lethal to bacteria without spurring antimicrobial resistance. However, it is very challenging to establish a quantifiable relationship between antibacterial efficacy and physical interactions such as mechanical and electrical forces. Herein, titanium nitride (TN) nanowires with adjustable orientations and capacitances are prepared to exert gradient electro-mechanical forces on bacteria. While vertical nanowires show the strongest mechanical force resulting in an antibacterial efficiency of 0.62 log reduction (vs 0.22 for tiled and 0.36 for inclined nanowires, respectively), the addition of electrical charges maximizes the electro-mechanical interactions and elevates the antibacterial efficacy to more than 3 log reduction. Biophysical and biochemical analyses indicate that electrostatic attraction by electrical charge narrows the interface. The electro-mechanical intervention more easily stiffens and rips the bacteria membrane, disturbing the electron balance and generating intracellular oxidative stress. The antibacterial ability is maintained in vivo and bacteria-challenged rats are protected from serious infection. The physical bacteria-killing process demonstrated here can be controlled by adjusting the electro-mechanical interactions. Overall, these results revealed important principles for rationally designing high-performance antibacterial interfaces for clinical applications.