Permeability Of Cytoplasmic Membrane Research Articles

Intraventricular haemorrhage in premature infants: the role of immature neuronal salt and water transport.

Intraventricular haemorrhage is a common complication of premature birth. Survivors are often left with cerebral palsy, intellectual disability and/or hydrocephalus. Animal models suggest that brain tissue shrinkage, with subsequent vascular stretch and tear, is an important step in the pathophysiology, but the cause of this shrinkage is unknown. Clinical risk factors for intraventricular haemorrhage are biomarkers of hypoxic-ischaemic stress, which causes mature neurons to swell. However, immature neuronal volume might shift in the opposite direction in these conditions. This is because immature neurons express the chloride, salt and water transporter NKCC1, which subserves regulatory volume increases in non-neural cells, whereas mature neurons express KCC2, which subserves regulatory volume decreases. When hypoxic-ischaemic conditions reduce active ion transport and increase the cytoplasmic membrane permeability, the effects of these transporters are diminished. Consequentially, mature neurons swell (cytotoxic oedema), whereas immature neurons might shrink. After hypoxic-ischaemic stress, in vivo and in vitro multi-photon imaging of perinatal transgenic mice demonstrated shrinkage of viable immature neurons, bulk tissue shrinkage and blood vessel displacement. Neuronal shrinkage was correlated with age-dependent membrane salt and water transporter expression using immunohistochemistry. Shrinkage of immature neurons was prevented by prior genetic or pharmacological inhibition of NKCC1 transport. These findings open new avenues of investigation for the detection of acute brain injury by neuroimaging, in addition to prevention of neuronal shrinkage and the ensuing intraventricular haemorrhage, in premature infants.

Synthesis and agricultural antimicrobial evaluation of new quinazoline derivatives containing both a piperazine linker and the N-acetyl moiety.

To discover more efficient agricultural antimicrobial agents, a series of new quinazoline derivatives containing both a piperazine linker and the N-acetyl moiety were prepared and assessed for their antibacterial and antifungal activities. All the target compounds were characterized by 1H and 13C NMR as well as high-resolution mass spectrometry (HRMS), and the chemical structure of the most potent compound E19 incorporating a 4-trifluoromethoxy substituent was clearly confirmed via single crystal X-ray diffraction measurements. The bioassay results indicated that some compounds possessed notable inhibitory effects in vitro against the bacterium Xanthomonas oryzae pv. oryzicola (Xoc). For example, compound E19 had an EC50 (effective concentration for 50% activity) value of 7.1 μg/mL towards this pathogen, approximately 15- and 10-fold more effective than the commercial bactericides thiodiazole copper and bismerthiazol (EC50 = 110.2 and 72.4 μg/mL, respectively). Subsequently, the mechanistic studies showed that compound E19 likely exerted its antibacterial efficacies by altering the cell morphology, increasing the permeability of bacterial cytoplasmic membrane, suppressing the production of bacterial extracellular polysaccharides and the extracellular enzyme activities (amylase and cellulase), and blocking the swimming motility of Xoc. Moreover, the proteomic analysis revealed that compound E19 could reduce the bacterial flagellar biosynthesis and decrease the flagellar motility by down-regulating the expression of the related differential proteins. Compound E19 exhibited good potential for further development as a bactericide candidate for control of Xoc. © 2024 Society of Chemical Industry.

Daidzein‐Based Amphiphilic Small Molecular Antimicrobial Peptidomimetics as Novel Antimicrobial Agents with Anti‐Biofilm Activity

AbstractA new series of daidzein‐based short peptidomimetic compounds were developed. In this study, we incorporated an alkyl chain with different chain lengths as hydrophobic groups, various amino acids and their respective guanidinium salts as hydrophilic groups. The most potent compound 9 a showed excellent antibacterial activity with minimum inhibitory concentration (MIC) of 8 μM against S. aureus and 32 μM against Escherichia coli. Furthermore, 9 a inhibited more than 65 % S. aureus biofilm formation at sub‐MIC, it also disrupted 69 % pre‐established S. aureus at 64 μM. The cytoplasmic membrane permeability study of 9 a revealed that the depolarization of membrane could be the possible mechanism of action. However, 9 a exhibited moderate toxicity against human erythrocytes.

Regulation of intracellular process by two-component systems: Exploring the mechanism of plasmid-mediated conjugative transfer

Plasmid-mediated conjugative transfer facilitates the dissemination of antibiotic resistance, yet the comprehensive regulatory mechanisms governing this process remain elusive. Herein, we established pure bacteria and activated sludge conjugation system to investigate the regulatory mechanisms of conjugative transfer, leveraging metformin as an exogenous agent. Transcriptomic analysis unveiled that substantial upregulation of genes associated with the two-component system (e.g., AcrB/AcrA, EnvZ/Omp, and CpxA/CpxR) upon exposure to metformin. Furthermore, downstream regulators of the two-component system, including reactive oxygen species (ROS), cytoplasmic membrane permeability, and adenosine triphosphate (ATP) production, were enhanced by 1.7, 1.4 and 1.1 times, respectively, compared to the control group under 0.1 mg/L metformin exposure. Moreover, flow sorting and high-throughput sequencing revealed increased microbial community diversity among transconjugants in activated sludge systems. Notably, the antibacterial potential of human pathogenic bacteria (e.g., Bacteroides, Escherichia-Shigella, and Lactobacillus) was augmented, posing a potential threat to human health. Our findings shed light on the spread of antibiotic resistance bacteria and assess the ecological risks associated with plasmid-mediated conjugative transfer in wastewater treatment systems.

Dimeric peptoids as antibacterial agents

Building upon our previous study on peptoid-based antibacterials which showed good activity against Gram-positive bacteria only, herein we report the synthesis of 34 dimeric peptoid compounds and the investigation of their activity against Gram-positive and Gram-negative pathogens. The newly designed peptoids feature a di-hydrophobic moiety incorporating phenyl, bromo-phenyl, and naphthyl groups, combined with variable lengths of cationic units such as amino and guanidine groups. The study also underscores the pivotal interplay between hydrophobicity and cationicity in optimizing efficacy against specific bacteria. The bromophenyl dimeric guanidinium peptoid compound 10j showed excellent activity against S. aureus 38 and E. coli K12 with MIC of 0.8 μg mL−1 and 6.2 μg mL−1, respectively. Further investigation into the mechanism of action revealed that the antibacterial effect might be attributed to the disruption of bacterial cell membranes, as suggested by tethered bilayer lipid membranes (tBLMs) and cytoplasmic membrane permeability studies. Notably, these promising antibacterial agents exhibited negligible toxicity against mammalian red blood cells. Additionally, the study explored the potential of 12 active compounds to disrupt established biofilms of S. aureus 38. The most effective biofilm disruptors were ethyl and octyl-naphthyl guanidinium peptoids (10c and 10 k). These compounds 10c and 10 k disrupted the established biofilms of S. aureus 38 with 51 % at 4x MIC (MIC = 17.6 μg mL−1 and 11.2 μg mL−1) and 56 %-58 % at 8x MIC (MIC = 35.2 μg mL−1 and 22.4 μg mL−1) respectively. Overall, this research contributes insights into the design principles of cationic dimeric peptoids and their antibacterial activity, with implications for the development of new antibacterial compounds.

The synergistic antibacterial activity and mechanism of colistin-oxethazaine combination against gram-negative pathogens.

The rapid spread of bacteria with plasmid-mediated resistance to antibiotics poses a serious threat to public health. The search for potential compounds that can increase the antibacterial activity of existing antibiotics is a promising strategy for addressing this issue. Synergistic activity of the FDA-approved agent oxethazine combined with colistin was investigated in vitro using checkerboard assays and time-kill curves. The synergistic mechanisms of their combination of oxethazine and colistin was explored by fluorescent dye, scanning electron microscopy (SEM) and LC-MS/MS. The synergistic efficacy was evaluated in vivo by the Galleria mellonella and mouse sepsis models. In this study, we found that oxethazine could effectively enhance the antibacterial activity of colistin against both mcr-positive and -negative pathogens, and mechanistic assays revealed that oxethazine could improve the ability of colistin to destruct bacterial outer membrane and cytoplasmic membrane permeability. In addition, their combination triggered the accumulation of reactive oxygen species causing additional damage to the membrane structure resulting in cell death. Furthermore, oxethazine significantly enhanced the therapeutic efficacy of colistin in two animal models. These results suggested that oxethazine, as a promising antibiotic adjuvant, can effectively enhance colistin activity, providing a potential strategy for treating multidrug-resistant bacteria.

Antimicrobial effects of Cinnamomum verum essential oil against Enterococcus faecalis and Staphylococcus aureus in mulberry and carrot juices

SummaryIn developing countries, fresh fruit juices are prepared and sold without ongoing assessment of the quality and safety of mulberry and carrot juices. Therefore, most fruit juices offered for consumption had high microbial content. This investigation was performed to indicate the efficacy of low concentrations of Cinnamomum verum essential oils (CEO) in the inactivation of E. faecalis and S. aureus in carrot juice and white mulberry juice and the impact on the sensorial characteristics of the juices. CEO antimicrobial activity can prevent the growth of Staphylococcus aureus and Enterococcus faecalis at 12 and 4 °C in juices. For the MIC and MBC concentrations, CEO exhibited higher antibacterial effects against S. aureus and E. faecalis. A higher number of pathogens were inactivated at 12 °C than at 4 °C. Cytoplasmic membrane permeability plays a vital role in the CEO bactericidal action. CEO can be recommended to extend the shelf‐life of juices by retaining the sensorial quality and inactivating pathogenic microorganisms, which provides a reference for practical production and application.

Evaluation of the Effect of Plectranthus amboinicus L. Leaf Extracts on the Bacterial Antioxidant System and Cell Membrane Integrity of Pseudomonas aeruginosa PA01 and Staphylococcus aureus NCTC8325.

Plectranthus amboinicus (Indian borage) has been extensively studied for its medicinal properties, which can be exploited to develop new antimicrobial therapeutics. The current study investigated the effect of Plectranthus amboinicus leaf extracts on the catalase activity, reactive oxygen species, lipid peroxidation, cytoplasmic membrane permeability, and efflux pump activity in S. aureus NCTC8325 and P. aeruginosa PA01. As the enzyme catalase protects bacteria against oxidative stress, disruption of its activity creates an imbalance in reactive oxygen species (ROS) levels, which subsequently oxidizes lipid chains, leading to lipid peroxidation. In addition, bacterial cell membranes are a potential target for new antibacterial agents, as efflux pump systems play a crucial role in antimicrobial resistance. Upon exposure of the microorganisms to Indian borage leaf extracts, the observed catalase activity decreased by 60% and 20% in P. aeruginosa and S. aureus, respectively. The generation of ROS can cause oxidation reactions to occur within the polyunsaturated fatty acids of the lipid membranes and induce lipid peroxidation. To investigate these phenomena, the increase in ROS activity in P. aeruginosa and S. aureus was studied using H2DCFDA, which is oxidized to 2',7'-dichlorofluorescein (DCF) by ROS. Furthermore, the concentration of lipid peroxidation product (malondialdehyde) was assessed using the Thiobarbituric acid assay and was shown to increase by 42.4% and 42.5% in P. aeruginosa and S. aureus, respectively. The effect of the extracts on the cell membrane permeability was monitored using diSC3-5 dye and it was observed that the cell membrane permeability of P. aeruginosa increased by 58% and of S. aureus by 83%. The effect on efflux pump activity was investigated using Rhodamine-6-uptake assay, which displayed a decrease in efflux activity of 25.5% in P. aeruginosa and 24.2% in S. aureus after treatment with the extracts. This combination of different methods to study various bacterial virulence factors provides a more robust, mechanistic understanding of the effect of P. amboinicus extracts on P. aeruginosa and S. aureus. This study thus represents the first report of the assessment of the effect of Indian borage leaf extracts on bacterial antioxidant systems and bacterial cell membranes, and can facilitate the future development of bacterial resistance modifying agents derived from P. amboinicus.

Synergistic Interaction between Boesenbergia rotunda (L.) Mansf. Essential Oil and Cloxacillin on Methicillin-Resistant Staphylococcus aureus (MRSA) Inhibition.

Currently, antibiotic resistance is widespread among bacteria. This problem requires greater awareness because bacterial resistance increases, reducing antibiotic use effectiveness. Consequently, new alternative treatments are needed because the treatment options for these bacteria are limited. This work aims to determine the synergistic interaction and mechanism of action of Boesenbergia rotunda essential oil (BREO) against methicillin-resistant Staphylococcus aureus (MRSA). Gas chromatography-mass spectrometry identified 24 BREO chemicals (GC-MS). The main components of BREO were β-ocimene (36.73%), trans-geraniol (25.29%), camphor (14.98%), and eucalyptol (8.99%). BREO and CLX inhibited MRSA DMST 20649, 20651, and 20652 with a minimum inhibitory concentration (MIC) of 4 mg/mL and 512 µg/mL, respectively. The checkerboard method and the time-kill assay revealed synergy between BREO and CLX with fractional inhibitory concentration (FIC) <0.5 and log reduction >2log10 CFU/mL at 24 hours compared to the most effective chemical. BREO inhibited biofilm formation and increased membrane permeability. Exposure alone to BREO or in combination with CLX inhibited biofilm formation and increased cytoplasmic membrane (CM) permeability. The scanning electron microscopy (SEM) and transmission electron microscopy (TEM) results revealed that alterations in the cell walls, cytoplasmic membrane, and leakage of intracellular components of MRSA DMST 20651 after treatment with BREO alone and in combination with CLX were observed. These results indicate that BREO synergizes and could reverse the antibacterial activity of CLX against MRSA strains. The synergy of BREO may lead to novel drug combinations that increase the effectiveness of antibiotics against MRSA.

Short Tryptamine-Based Peptoids as Potential Therapeutics for Microbial Keratitis: Structure-Function Correlation Studies.

Peptoids are peptidomimetics that have attracted considerable interest as a promising class of antimicrobials against multi-drug-resistant bacteria due to their resistance to proteolysis, bioavailability, and thermal stability compared to their corresponding peptides. Staphylococcus aureus is a significant contributor to infections worldwide and is a major pathogen in ocular infections (keratitis). S. aureus infections can be challenging to control and treat due to the development of multiple antibiotic resistance. This work describes short cationic peptoids with activity against S. aureus strains from keratitis. The peptoids were synthesized via acid amine-coupling between naphthyl-indole amine or naphthyl-phenyl amine with different amino acids to produce primary amines (series I), mono-guanidines (series II), tertiary amine salts (series III), quaternary ammonium salts (series IV), and di-guanidine (series V) peptoids. The antimicrobial activity of the peptoids was compared with ciprofloxacin, an antibiotic that is commonly used to treat keratitis. All new compounds were active against Staphylococcus aureus S.aureus 38. The most active compounds against S.aur38 were 20a and 22 with MIC = 3.9 μg mL−1 and 5.5 μg mL−1, respectively. The potency of these two active molecules was investigated against 12 S. aureus strains that were isolated from microbial keratitis. Compounds 20a and 22 were active against 12 strains with MIC = 3.2 μg mL−1 and 2.1 μg mL−1, respectively. There were two strains that were resistant to ciprofloxacin (Sa.111 and Sa.112) with MIC = 128 μg mL−1 and 256 μg mL−1, respectively. Compounds 12c and 13c were the most active against E. coli, with MIC > 12 μg mL−1. Cytoplasmic membrane permeability studies suggested that depolarization and disruption of the bacterial cell membrane could be a possible mechanism for antibacterial activity and the hemolysis studies toward horse red blood cells showed that the potent compounds are non-toxic at up to 50 μg mL−1.

Synergistic antimicrobial activity of TZP4 with conventional antibiotics against antibiotic‐resistant Pseudomonas aeruginosa

AbstractWe recently synthesized a triazine‐derived amphipathic molecule, TZP4, which has potent antimicrobial activity against antibiotic‐resistant Pseudomonas aeruginosa (ARPA). Here, we investigated the synergistic antimicrobial effect of TZP4 in combination with four different conventional antibiotics each representing a distinct mechanism against ARPA. Checkerboard assay and time‐kill assays showed that the potent synergistic antimicrobial activity was observed only in TZP4/chloramphenicol and TZP4/ciprofloxacin combinations. Flow cytometry analysis for these combinations demonstrated that the synergistic antimicrobial activity was due to the increased permeability of bacterial cytoplasmic membrane. In addition, TZP4 was able to prevent and eradicate biofilms, which are one of the primary reasons for drug resistance caused by ARPA. Confocal laser scanning microscopy revealed that TZP4 significantly reduced mature ARPA biofilm biomass. Overall, our findings suggest that TZP4 is a potential adjuvant to antimicrobial chemotherapy and a potential antibiofilm agent to treat infections caused by ARPA.

Photo‐triggered polymeric antimicrobial peptide mimics with excellent selectivity and antifouling and antimicrobial hydrogels

Stimuli-responsive antimicrobial polymeric materials have received increasing interest. In this study, we synthesized a novel type of photoresponsive antimicrobial poly(ethyl glycol)-b-poly[N-[2-[N-(o-nitrobenzyloxycarbonyl)-amino]-ethyl]-glycine] (PEG-b-PN(oNB)G) diblock copolymer by ring-opening polymerization. Upon UV irradiation, the amine groups can be generated due to the photocleavage of the o-nitrobenzyl protecting groups. The cleavage degree can reach up to around 90% after 12 h UV irradiation. The copolymers exhibit excellent antimicrobial activity with a low minimal inhibitory concentration (MIC) value after UV irradiation. We demonstrate that this is possibly because of the balance of hydrophobicity and amphiphilicity arising from the remaining hydrophobic phenyl residues, which structurally mimic antimicrobial peptides (AMPs). We further demonstrate a disrupted cell membrane mechanism mimetic to AMPs by systematic studies of cytoplasmic membrane depolarization assay, cytoplasmic membrane permeabilization assay, bacterial morphology, and the interaction between the irradiated copolymer and the bacterial membrane by confocal laser scanning microscopy (CLSM). Remarkably, the obtained copolymers show excellent selectivity with extremely high HC5 values (> 2000 μg/mL). In addition, the photoresponsive polymers exhibit remarkable antimicrobial activity against multidrug-resistant S. aureus (MRSA), and high efficiency to inhibit the formation of MRSA biofilms and eradicate the mature MRSA biofilms. Further, we prepared the photoresponsive hydrogels by mixing with agarose, which results in a recyclable antimicrobial and nonfouling surface. The photoresponsive AMP-mimetic polymers and the biocompatible hydrogels with dual-functionalities show great potential for antimicrobial applications.

Determination of the Relationships between the Chemical Structure and Antimicrobial Activity of a GAPDH-Related Fish Antimicrobial Peptide and Analogs Thereof.

The structure–activity relationships and mode of action of synthesized glyceraldehyde-3-phosphate dehydrogenase (GAPDH)-related antimicrobial peptides were investigated. Including the native skipjack tuna GAPDH-related peptide (SJGAP) of 32 amino acid residues (model for the study), 8 different peptide analogs were designed and synthesized to study the impact of net charge, hydrophobicity, amphipathicity, and secondary structure on both antibacterial and antifungal activities. A net positive charge increase, by the substitution of anionic residues or C-terminal amidation, improved the antimicrobial activity of the SJGAP analogs (minimal inhibitory concentrations of 16–64 μg/mL), whereas the alpha helix content, as determined by circular dichroism, did not have a very definite impact. The hydrophobicity of the peptides was also found to be important, especially for the improvement of antifungal activity. Membrane permeabilization assays showed that the active peptides induced significant cytoplasmic membrane permeabilization in the bacteria and yeast tested, but that this permeabilization did not cause leakage of 260 nm-absorbing intracellular material. This points to a mixed mode of action involving both membrane pore formation and targeting of intracellular components. This study is the first to highlight the links between the physicochemical properties, secondary structure, antimicrobial activity, and mechanism of action of antimicrobial peptides from scombrids or homologous to GAPDH.

Negative Electrization of Air as a Means of Counteracting Airborne Viral Infections

Geneticists and genetic engineers, who constantly introduce nucleic acids into target cells, have experimentally proven that positive electrization of the external environment of cells increases the permeability of cell membranes to nucleic acids. Moreover, they experimentally found that those nucleic acids that are part of positively charged complexes, mostquickly penetrate into cells. Thus, the practical experience of geneticists and genetic engineers convincingly proves that the positive electrization of both the cellular environment and the objects present in it, increases the permeability of cytoplasmic membranes for the latter. Accordingly, all this suggests that the positive electrization of the internal environment of the human body promotes the penetration of foreign nucleic acids, especially viral, into its cells. Moreover, given the function of extracellular protons in creating a proton motive force that directs glucose into cells, it can be argued that the positive electrization of the external environment of human cells contributes to the reproduction of viruses in them. Accordingly, it can be expected that the negative electrization of the human internal environment should prevent both the penetration of viral nucleic acids into cells, and the reproduction of viruses there. Naturally, all this allows us to offer negative electrization of the air as the most affordable means to combat airborne viral infections. Offering such a means, we expect that the negative electrization of the air that a person inhales will lead to the same electrization of his internal environment, first of all – his respiratory tracts, which are the first to come into contact with viruses contained in the air. The validity of this offer is discussed here.

Composition and antifungal mechanism of essential oil from Chrysanthemum morifolium cv. Fubaiju

• Components of Chrysanthemum morifolium cv. Fubaiju essential oil (CMF-EO) were characterized. • CMF-EO showed excellent antifungal activities against six common fungus. • Antifungal targets were cell membrane, mitochondrial membrane, and DNA. • Multiple antifungal mechanisms make fungi difficult to develop drug resistance. Chrysanthemum morifolium cv. Fubaiju (CMF) has been used as a dietary herb in East Asia for centuries. The chemical composition and antifungal activity of CMF essential oil (CMF-EO) were investigated in this study. We have found that CMF-EO was a light-yellow, transparent liquid (0.61% yield, w/w) and majorly contain 31 volatile components with a total of 98.41% determined by GS and GC/MS. Camphor was the major compound (16.87%), followed by 1,8-cineole (10.62%), β -curcumene (9.51%), bornyl acetate (7.43%), α -zingiberene (6.97%), β-elemene (6.47%), α -bisabolol (4.74%), borneol (4.24%) and eugenol (4.23%). In addition, contents with more than 2% of the total CMF-EO were 1-caryophyllene (3.92%), chrysanthenyl acetate (3.29%), caryophyllene oxide (2.28%), and chamazulene (2.23%). Six fungal strains were used to study the antifungal activities and mechanisms of CMF-EO using fluorescence probe–membrane integrity assay, analysis of cytoplasmic membrane permeability, electron microscopy, monitoring of the effect of the mitochondrial membrane potential and DNA binding assay. CMF-EO effectively inhibited the growth of C. albicans , C. glabrata , C. tropicalis , S. cerevisiae , D. hansenii , and Z. parabailii with minimum inhibition concentrations of 31.25, 31.25, 62.5, 31.25, 15.625, and 15.625 μg/mL, respectively, and minimum fungicidal concentrations of 62.5, 125.0, 125.0, 62.5, 31.25, and 62.5 μg/mL, respectively. The elucidated antifungal mechanisms of CMF-EO included the destruction of cytoplasmic membrane and the damage of mitochondria and DNA. The multiple antifungal mechanisms made it difficult for fungi to develop drug resistance, and this finding might shed new light on the development of new fungal agents.

Polyphenylglyoxamide-Based Amphiphilic Small Molecular Peptidomimetics as Antibacterial Agents with Anti-Biofilm Activity.

The rapid emergence of drug-resistant bacteria is a major global health concern. Antimicrobial peptides (AMPs) and peptidomimetics have arisen as a new class of antibacterial agents in recent years in an attempt to overcome antibiotic resistance. A library of phenylglyoxamide-based small molecular peptidomimetics was synthesised by incorporating an N-alkylsulfonyl hydrophobic group with varying alkyl chain lengths and a hydrophilic cationic group into a glyoxamide core appended to phenyl ring systems. The quaternary ammonium iodide salts 16d and 17c showed excellent minimum inhibitory concentration (MIC) of 4 and 8 μM (2.9 and 5.6 μg/mL) against Staphylococcus aureus, respectively, while the guanidinium hydrochloride salt 34a showed an MIC of 16 μM (8.5 μg/mL) against Escherichia coli. Additionally, the quaternary ammonium iodide salt 17c inhibited 70% S. aureus biofilm formation at 16 μM. It also disrupted 44% of pre-established S. aureus biofilms at 32 μM and 28% of pre-established E. coli biofilms 64 μM, respectively. A cytoplasmic membrane permeability study indicated that the synthesised peptidomimetics acted via disruption and depolarisation of membranes. Moreover, the quaternary ammonium iodide salts 16d and 17c were non-toxic against human cells at their therapeutic dosages against S. aureus.

Antibacterial Activity of Lupinifolin from Derris reticulata and Its Effect on Cytoplasmic Membrane of Methicillin Resistant

Lupinifolin from Derris reticulata Craib. was extracted with hexane by Soxhlet extractor and purified by crystallization. The yellow needle-shaped lupinifolin crystals were identified and confirmed by nuclear magnetic resonance (NMR) spectra and Liquid chromatography mass spectrometry (LC/MS). The lupinifolin showed minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) of 8 and 16 µg/ml against Methicillin resistant S. aureus (MRSA), respectively. The flow cytometry (FCM) was performed to determine the alteration of cytoplasmic membrane (CM) permeability of MRSA by using Propidium iodide (PI) 5 µg/ml as an indicator for bacterial membrane integrity. It was found that the bacterial CM permeability was effected by lupinifolin with the MIC of 8 µg/ml comparable to the control when investigated by Propidium iodide intensity. Additionally, DNA laddering assay was carried out to evaluate apoptosis in bacterial cells. It was shown that the lupinifolin has no effect on DNA fragmentation.

Design, Synthesis and Biological Evaluation of Biphenylglyoxamide-Based Small Molecular Antimicrobial Peptide Mimics as Antibacterial Agents.

There has been an increasing interest in the development of antimicrobial peptides (AMPs) and their synthetic mimics as a novel class of antibiotics to overcome the rapid emergence of antibiotic resistance. Recently, phenylglyoxamide-based small molecular AMP mimics have been identified as potential leads to treat bacterial infections. In this study, a new series of biphenylglyoxamide-based small molecular AMP mimics were synthesised from the ring-opening reaction of N-sulfonylisatin bearing a biphenyl backbone with a diamine, followed by the conversion into tertiary ammonium chloride, quaternary ammonium iodide and guanidinium hydrochloride salts. Structure–activity relationship studies of the analogues identified the octanesulfonyl group as being essential for both Gram-positive and Gram-negative antibacterial activity, while the biphenyl backbone was important for Gram-negative antibacterial activity. The most potent analogue was identified to be chloro-substituted quaternary ammonium iodide salt 15c, which possesses antibacterial activity against both Gram-positive (MIC against Staphylococcus aureus = 8 μM) and Gram-negative bacteria (MIC against Escherichia coli = 16 μM, Pseudomonas aeruginosa = 63 μM) and disrupted 35% of pre-established S. aureus biofilms at 32 μM. Cytoplasmic membrane permeability and tethered bilayer lipid membranes (tBLMs) studies suggested that 15c acts as a bacterial membrane disruptor. In addition, in vitro toxicity studies showed that the potent compounds are non-toxic against human cells at therapeutic dosages.

WITHDRAWN: Novel long-acting BF-30 conjugate corrects pancreatic carcinoma via cytoplasmic membrane permeabilization and DNA-binding in tumor-bearing mice

This article has been withdrawn at the request of the editor. The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at https://www.elsevier.com/about/our-business/policies/article-withdrawal.

Antinociceptive and Antimicrobial Activity of Products from Reactions of Pyrrolobenzoxazinetriones with Thiosemicarbazones of Aromatic and Heteroaromatic Aldehydes

Previously, a series of hetareno[e]pyrrole-2,3-diones was found to include compounds with high antimicrobial and antinociceptive activity and low toxicity, so that new hetareno[e]pyrrole-2,3-dione derivatives were expected to have these types of activity. The reactions of pyrrolobenzoxazinetriones with a series of aromatic aldehyde thiosemicarbazones and nicotinic aldehyde thiosemicarbazone are reported. Results from studies of the antinociceptive (hot-plate test) and antimicrobial activity (Staphylococcus aureus No. 906, Escherichia coli No. 1257) are given. The most active compounds were effective on the level of the reference drugs. The target of the antinociceptive activity of the tested compounds was considered nerve endings because signs of central action were not observed in the behavior of animals under the influence of the compounds. The selective antimicrobial activity against Gram-positive bacteria S. aureus was presumably associated with disruption of the cytoplasmic membrane permeability and bacterial RNA synthesis.