Clinical use of 2-deoxystreptamine aminoglycoside antibiotics, which target the bacterial ribosome, is compromised by adverse effects related to limited drug selectivity. Here we present a series of 4',6'-O-acetal and 4'-O-ether modifications on glucopyranosyl ring I of aminoglycosides. Chemical modifications were guided by measuring interactions between the compounds synthesized and ribosomes harbouring single point mutations in the drug-binding site, resulting in aminoglycosides that interact poorly with the drug-binding pocket of eukaryotic mitochondrial or cytosolic ribosomes. Yet, these compounds largely retain their inhibitory activity for bacterial ribosomes and show antibacterial activity. Our data indicate that 4'-O-substituted aminoglycosides possess increased selectivity towards bacterial ribosomes and little activity for any of the human drug-binding pockets.
Doripenem is approved in the Asia-Pacific (APAC) region for treating nosocomial pneumonia (NP) including ventilator-associated pneumonia (VAP), complicated intra-abdominal infections (cIAIs) and complicated urinary tract infections (cUTIs). Clinical usage of doripenem (500mg intravenously, infused over 1h or 4h every 8h for 5-14 days) in APAC was evaluated in a prospective, open-label, non-comparative, multicentre study of inpatients (≥18 years) with NP, VAP, cIAI or cUTI. A total of 216 [intention-to-treat (ITT)] patients received doripenem: 53 NP (24.5%); 77 VAP (35.6%); 67 cIAI (31.0%); and 19 cUTI (8.8%). Doripenem MIC90 values for Pseudomonas aeruginosa, Acinetobacter baumannii, Escherichia coli and Klebsiella pneumoniae were 32, 32, 0.094 and 0.64μg/mL, respectively. Doripenem was used most commonly as monotherapy (86.6%) and as second-line therapy (62.0%). The clinical cure rate in clinically evaluable patients was 86.7% at the end of therapy (EOT) and 87.1% at test of cure (TOC) (7-14 days after EOT). In the ITT population, overall clinical cure rates were 66.2% at EOT and 56.5% at TOC. The median duration of hospital stay, intensive care unit (ICU) stay and mechanical ventilation was 20, 12 and 10 days, respectively. Of 146 discharged patients, 7 were re-admitted within 28 days of EOT; 1 VAP patient was re-admitted to the ICU. The all-cause mortality rate was 22.7% (49/216). The most common treatment-related adverse events were diarrhoea (1.4%) and vomiting (1.4%). Doripenem is a viable option for treating APAC patients with NP, VAP, cIAI or cUTI. [ClinicalTrials.gov: NCT 00986102].
Green synthesis of ZnO nanoparticles (NPs) using the plants' extract and their potential application have driven a tremendous interest in recent years. This study reports a green microwave-assisted method for synthesis of ZnO NPs using Silybum marianum L. seed extract. Characteristics of the as-prepared sample was explored in terms of crystalline phase, morphology, composition, surface area, optical, and thermal properties. The particles of the biosynthesized sample (ZnO/extract) had smaller sizes than the chemically produced one (ZnO). The existence of biomolecules from Silybum marianum L seed extract linked to the ZnO/extract sample was approved by various analyses. The ZnO/extract sample was used for treating alloxan-induced diabetic rats and its efficiency was compared with ZnO, extract, and insulin treatments. For this purpose, the levels of blood glucose, insulin, total cholesterol, total triglyceride, and high-density lipoprotein were measured before and after treating with the studied treatment agents and compared with each other. Moreover, the antibacterial activities of both ZnO samples were investigated against E. coli to assess their potential antibacterial application. From the results, ZnO/extract NPs represented an outstanding performance in overcoming the diabetic disorders and good antibacterial activity against the studied bacteria.
Polymyxin B and colistin were examined for their ability to inhibit the type II NADH-quinone oxidoreductases (NDH-2) of three species of Gram-negative bacteria. Polymyxin B and colistin inhibited the NDH-2 activity in preparations from all of the isolates in a concentration-dependent manner. The mechanism of NDH-2 inhibition by polymyxin B was investigated in detail with Escherichia coli inner membrane preparations and conformed to a mixed inhibition model with respect to ubiquinone-1 and a non-competitive inhibition model with respect to NADH. These suggest that the inhibition of vital respiratory enzymes in the bacterial inner membrane represents one of the secondary modes of action for polymyxins.
Actinopyga lecanora, a type of sea cucumber commonly known as stone fish with relatively high protein content, was explored as raw material for bioactive peptides production. Six proteolytic enzymes, namely alcalase, papain, pepsin, trypsin, bromelain and flavourzyme were used to hydrolyze A. lecanora at different times and their respective degrees of hydrolysis (DH) were calculated. Subsequently, antibacterial activity of the A. lecanora hydrolysates, against some common pathogenic Gram positive bacteria (Bacillus subtilis and Staphylococcus aureus) and Gram negative bacteria (Escherichia coli, Pseudomonas aeruginosa, and Pseudomonas sp.) were evaluated. Papain hydrolysis showed the highest DH value (89.44%), followed by alcalase hydrolysis (83.35%). Bromelain hydrolysate after one and seven hours of hydrolysis exhibited the highest antibacterial activities against Pseudomonas sp., P. aeruginosa and E. coli at 51.85%, 30.07% and 30.45%, respectively compared to the other hydrolysates. Protein hydrolysate generated by papain after 8 h hydrolysis showed maximum antibacterial activity against S. aureus at 20.19%. The potent hydrolysates were further fractionated using RP-HPLC and antibacterial activity of the collected fractions from each hydrolysate were evaluated, wherein among them only three fractions from the bromelain hydrolysates exhibited inhibitory activities against Pseudomonas sp., P. aeruginosa and E. coli at 24%, 25.5% and 27.1%, respectively and one fraction of papain hydrolysate showed antibacterial activity of 33.1% against S. aureus. The evaluation of the relationship between DH and antibacterial activities of papain and bromelain hydrolysates revealed a meaningful correlation of four and six order functions.
An incredible amount of joss fly ash is produced from the burning of Chinese holy joss paper; thus, an excellent method of recycling joss fly ash waste to extract aluminosilicate nanocomposites is explored. The present research aims to introduce a novel method to recycle joss fly ash through a simple and straightforward experimental procedure involving acidic and alkaline treatments. The synthesized aluminosilicate nanocomposite was characterized to justify its structural and physiochemical characteristics. A morphological analysis was performed with field-emission transmission electron microscopy, and scanning electron microscopy revealed the size of the aluminosilicate nanocomposite to be ~25 nm, while also confirming a uniformly spherical-shaped nanostructure. The elemental composition was measured by energy dispersive spectroscopy and revealed the Si to Al ratio to be 13.24 to 7.96, showing the high purity of the extracted nanocomposite. The roughness and particle distribution were analyzed using atomic force microscopy and a zeta analysis. X-ray diffraction patterns showed a synthesis of faceted and cubic aluminosilicate crystals in the nanocomposites. The presence of silica and aluminum was further proven by X-ray photoelectron spectroscopy, and the functional groups were recognized through Fourier transform infrared spectroscopy. The thermal capacity of the nanocomposite was examined by a thermogravimetric analysis. In addition, the research suggested the promising application of aluminosilicate nanocomposites as drug carriers. The above was justified by an enzyme-linked apta-sorbent assay, which claimed that the limit of the aptasensing aluminosilicate-conjugated ampicillin was two-fold higher than that in the absence of the nanocomposite. The drug delivery property was further justified through an antibacterial analysis against Escherichia coli (gram-negative) and Bacillus subtilis (gram-positive).
This study aimed to investigate the mechanism of action of the cinnamon bark essential oil (CB), when used singly and also in combination with piperacillin, for its antimicrobial and synergistic activity against beta-lactamase TEM-1 plasmid-conferred Escherichia coli J53 R1. Viable count of this combination showed a complete killing profile at 20 h and further confirmed its synergistic effect by reducing the bacteria cell numbers. Analysis on the stability of treated cultures for cell membrane permeability by CB when tested against sodium dodecyl sulfate revealed that the bacterial cell membrane was disrupted by the essential oils. Scanning electron microscopy observation and bacterial surface charge measurement also revealed that CB causes irreversible membrane damage and reduces the bacterial surface charge. In addition, bioluminescence expression of Escherichia coli [pSB1075] and E. coli [pSB401] by CB showed reduction, indicating the possibility of the presence of quorum sensing (QS) inhibitors. Gas-chromatography and mass spectrometry of the essential oil of Cinnamomum verum showed that trans-cinnamaldehyde (72.81%), benzyl alcohol (12.5%), and eugenol (6.57%) were the major components in the essential oil. From this study, CB has the potential to reverse E. coli J53 R1 resistance to piperacillin through two pathways; modification in the permeability of the outer membrane or bacterial QS inhibition.
Phoenix dactylifera or date palm fruits are reported to contain natural compounds that exhibit antioxidant and antibacterial properties. This research aimed to study the effect of fruit chilling at 4 °C for 8 weeks, extract storage at -20 °C for 5 weeks, and extraction solvents (methanol or acetone) on total phenolic content (TPC), antioxidant activity and antibacterial properties of Saudi Arabian P. dactylifera cv Mabroom, Safawi and Ajwa, as well as Iranian P. dactylifera cv Mariami. The storage stability of total anthocyanin content (TAC) was also evaluated, before and after storing the extracts at -20 °C and 4 °C respectively, for 5 weeks. Mariami had the highest TAC (3.18 ± 1.40 mg cyd 3-glu/100 g DW) while Mabroom had the lowest TAC (0.54 ± 0.15 mg cyd 3-glu/100 g DW). The TAC of all extracts increased after storage. The chilling of date palm fruits for 8 weeks prior to solvent extraction elevated the TPC of all date fruit extracts, except for methanolic extracts of Mabroom and Mariami. All IC50 values of all cultivars decreased after the fruit chilling treatment. Methanol was a better solvent compared to acetone for the extraction of phenolic compounds in dates. The TPC of all cultivars extracts decreased after 5 weeks of extract storage. IC50 values of all cultivars extracts increased after extract storage except for the methanolic extracts of Safawi and Ajwa. Different cultivars exhibited different antibacterial properties. Only the methanolic extract of Ajwa exhibited antibacterial activity against all four bacteria tested: Staphylococcus aureus, Bacillus cereus, Serratia marcescens and Escherichia coli. These results could be useful to the nutraceutical and pharmaceutical industries in the development of natural compound-based products.
The major l-amino acid oxidase (LAAO, EC 1.4.3.2) of king cobra (Ophiophagus hannah) venom is known to be an unusual form of snake venom LAAO as it possesses unique structural features and unusual thermal stability. The antibacterial effects of king cobra venom LAAO were tested against several strains of clinical isolates including Staphylococcus aureus, Staphylococcus epidermidis, Pseudomonas aeruginosa, Klebsiella pneumoniae, and Escherichia coli using broth microdilution assay. For comparison, the antibacterial effects of several antibiotics (cefotaxime, kanamycin, tetracycline, vancomycin and penicillin) were also examined using the same conditions. King cobra venom LAAO was very effective in inhibiting the two Gram-positive bacteria (S. aureus and S. epidermidis) tested, with minimum inhibitory concentration (MIC) of 0.78μg/mL (0.006μM) and 1.56μg/mL (0.012μM) against S. aureus and S. epidermidis, respectively. The MICs are comparable to the MICs of the antibiotics tested, on a weight basis. However, the LAAO was only moderately effective against three Gram-negative bacteria tested (P. aeruginosa, K. pneumoniae and E. coli), with MIC ranges from 25 to 50μg/mL (0.2-0.4μM). Catalase at the concentration of 1mg/mL abolished the antibacterial effect of LAAO, indicating that the antibacterial effect of the enzyme involves generation of hydrogen peroxide. Binding studies indicated that king cobra venom LAAO binds strongly to the Gram-positive S. aureus and S. epidermidis, but less strongly to the Gram-negative E. coli and P. aeruginosa, indicating that specific binding to bacteria is important for the potent antibacterial activity of the enzyme.
This study was carried out to evaluate the antibacterial activity of aqueous and organic extracts of Thymus capitatus L. (Lamiaceae) leaves and stems. Dried ground powder leaves and stems were extracted with water (aqueous extracts), ethanol, dichloromethane and hexane (Soxhlet extracts). The antibacterial activity of these extracts was evaluated against bacteria using disc diffusion method. The result obtained showed that the leaves had stronger antibacterial activity than the stems extracts. The ethanolic extract had the highest yield products and the high antibacterial activity than all other solvents. The results suggest that essential oil as non-polar organic compounds could be the main active compounds in this plant. Therefore the antibacterial activity of leaves ethanol extracts (LEE) was compared with essential oils leaves extracts (LEO) of T. capitatus. The LEO showed greater antibacterial activity than LEE. The LEO showed a broad spectrum of antibacterial activity and the Pseudomonas aeruginosa was the most sensitive bacteria.
Antibacterial activity of honey is mainly dependent on a combination of its peroxide activity and non-peroxide components. This study aims to investigate antibacterial activity of five varieties of Malaysian honey (three monofloral; acacia, gelam and pineapple, and two polyfloral; kelulut and tualang) against Staphylococcus aureus, Bacillus cereus, Escherichia coli, and Pseudomonas aeruginosa.
In this study, a comparative study of effect using honey on copper nanoparticles (Cu-NPs) via simple, environmentally friendly process and inexpensive route was reported. Honey and ascorbic acid act as stabilizing and reducing agents with the assistance of sonochemical method. The products were characterized using UV-visible (UV-vis) spectroscopy, X-Ray Diffraction (XRD), High-Resolution Transmission Electron Microscopy (HRTEM), Field-Emission Scanning Electron Microscopy (FESEM) and Fourier Transform Infrared (FTIR) spectroscopy. The reddish brown colour demonstrated the formation of Cu-NPs and UV-visible proved the plasmon resonance of Cu-NPs. XRD also confirmed a highly pure Cu-NPs obtained with absence of copper oxide in which the structure is crystalline. The spherical size of the Cu-NPs was acquire in the presence of honey which is 3.68 ± 0.78 nm with narrow particle distribution. The antibacterial activity was seen against gram-positive and gram-negative bacteria which are Enterococcus faecalis (E. faecalis) and Escherichia coli (E. coli). At higher concentration of Cu-NPs, they were more effective in killing both bacteria. The Cu-NPs without and with honey exhibited toxicities toward normal and cancerous cells. However, Cu-NPs without honey showed more potent killing activity against normal and cancer cells.
In this article, gelatin/copper activated faujasites (CAF) composite scaffolds were fabricated by lyophilisation technique for promoting partial thickness wound healing. The optimised scaffold with 0.5% (w/w) of CAF, G (0.5%), demonstrated pore size in the range of 10-350 μm. Agar disc diffusion tests verified the antibacterial role of G (0.5%) and further supported that bacterial lysis was due to copper released from the core of CAF embedded in the gelatin matrix. The change in morphology of bacteria as a function of CAF content in gelatin scaffold was studied using SEM analysis. The confocal images revealed the increase in mortality rate of bacteria with increase in concentration of incorporated CAF in gelatin matrix. Proficient oxygen supply to needy cells is a continuing hurdle faced by tissue engineering scaffolds. The dissolved oxygen measurements revealed that CAF embedded in the scaffold were capable of increasing oxygen supply and thereby promote cell proliferation. Also, G (0.5%) exhibited highest cell viability on NIH 3T3 fibroblast cells which was mainly attributed to the highly porous architecture and its ability to enhance oxygen supply to cells. In vivo studies conducted on Sprague Dawley rats revealed the ability of G (0.5%) to promote skin regeneration in 20 days. Thus, the obtained data suggest that G (0.5%) is an ideal candidate for wound healing applications.
The marine soft corals Sarcophyton trocheliophorum crude extracts possessed antimicrobial activity towards pathogenic bacterial strains, i.e. Bacillus cereus, Salmonella typhi, Escherichia coli, Staphylococcus aureus and Pseudomonas aeruginosa. Bioassay-guided fractionation indicated that the antimicrobial effect was due to the presence of terpenoid bioactive derivatives. Further biological assays of the n-hexane fractions were carried out using turbidity assay, inhibition zone assay and minimum inhibitory concentration for investigating the growth-inhibition effect towards the Gram-positive and Gram-negative bacteria. The fractions were screened and the structure of the isolated compound was justified by interpretation of the spectroscopic data, mainly mass spectrometry (GC-MS). The structure was assigned as (5S)-3-[(3E,5S)-5-hydroxy-3-hepten-6-yn-1-yl]-5-methyl-2(5H)-furanone and was effective at concentrations as low as 0.20 mg/mL. The above findings, in the course of our ongoing research on marine products, may implicate that the profound anti-microbial activity of the S. trocheliophorum soft corals, inhabiting the red sea reefs, is attributed to the presence of growth-inhibiting secondary metabolites mainly terpenoids.
This study aimed to develop a novel electrospun polyacrylonitrile (PAN) nanofiber membrane with the enhanced antibacterial property. The PAN nanofiber membrane was first subjected to alkaline hydrolysis treatment, and the treated membrane was subsequently grafted with chitosan (CS) to obtain a CS-modified nanofiber membrane (P-COOH-CS). The modified membrane was then coupled with different dye molecules to form P-COOH-CS-Dye membranes. Lastly, poly(hexamethylene biguanide) hydrochloride (PHMB) was immobilized on the modified membrane to produce P-COOH-CS-Dye-PHMB. Physical characterization studies were conducted on all the synthesized nanofiber membranes. The antibacterial efficacies of nanofiber membranes prepared under different synthesis conditions were evaluated systematically. Under the optimum synthesis conditions, P-COOH-CS-Dye-PHMB was highly effective in disinfecting a high concentration of Escherichia coli, with an antibacterial efficacy of approximately 100%. Additionally, the P-COOH-CS-Dye-PHMB exhibited an outstanding wash durability as its antibacterial efficacy was only reduced in the range of 5%-7% even after 5 repeated cycles of treatment. Overall, the experimental results of this study suggested that the P-COOH-CS-Dye-PHMB is a promising antibacterial nanofiber membrane that can be adopted in the food, pharmaceutical, and textile industries.
N-[(2-hydroxyl-3-trimethylammonium) propyl] chitosan chloride (HTCC), which is a type of chitosan derivative with quaternary ammonium groups, possesses a higher antibacterial activity as compared to the pristine chitosan. The nanofiber membranes made of HTCC are attractive for applications demanding for antibacterial function. However, the hydrophilic nature of HTCC makes it unsuitable for electrospinning of nanofibers. Hence, biodegradable polyvinyl alcohol (PVA) was proposed as an additive to improve the electrospinnability of HTCC. In this work, PVA/HTCC nanofiber membrane was crosslinked with the blocked diisocyanate (BI) to enhance the stability of nanofiber membrane in water. Microbiological assessments showed that the PVA/HTCC/BI nanofiber membranes possessed a good antibacterial efficacy (∼100 %) against E. coli. Moreover, the biocompatibility of PVA/HTCC/BI nanofiber membrane was proven by the cytotoxicity test on mouse fibroblasts. These promising results indicated that the PVA/HTCC/BI nanofiber membrane can be a promising material for food packaging and as a potential wound dressing for skin regeneration.
Biofilms are complex microbial communities that tend to attach to either biotic or abiotic surface. Enclosed in a self-produced extracellular polymeric substance (EPS) matrix, the biofilms often cause persistent infections. The objective of this study was to investigate the antibiofilm activity of dimethyl sulfoxide (DMSO) and afatinib against Gram-negative pathogens. Test microorganisms used in this study were Escherichia coli ATCC 1299, Pseudomonas aeruginosa ATCC 10145, and Salmonella typhimurium ATCC 14028. Biofilms were developed in 96-well microplate at 37°C for 24 h. Following removal of non-adherent cells, analysis of biofilm viability, biofilm biomass, and extracellular polymeric substances (EPS) matrix were performed using resazurin assay, crystal violet assay, and attenuated total reflectance fourier transform infrared (ATR-FTIR) spectroscopy, respectively. Bradford protein assay was conducted to determine the total amount of EPS proteins. The results demonstrated that both 32% DMSO alone and its combination with 3.2 μg/mL afatinib were effective in killing biofilm cells and reducing biofilm biomass. IR spectral variations of EPS matrix of biofilms in the range between 1700 and 900 cm-1 were also observed. Reduction in EPS proteins verified the chemical modifications of EPS matrix. In conclusion, 32% DMSO alone and its combination with 3.2 μg/mL afatinib showed remarkable antibiofilm activities against Gram-negative pathogens. It was suggested that the biofilm inhibition was mediated by the chemical modification of EPS matrix.
The pattern of antibiotic resistance amongst gram-negative bacteria (GNB) in paediatric units, which have heavy empirical usage of broad-spectrum antibiotics, was studied prospectively over a 6-month period. A total of 200 consecutive, non-duplicate gram-negative isolates were obtained from 109 patients admitted to intensive care and oncology units in two hospitals. The commonest isolates were Klebsiella spp (36.5 per cent) and Pseudomonas (20.0 per cent). The isolates showed lower susceptibility rates to the third-generation cephalosporins (47-62 per cent) compared with cefepime (91 per cent), imipenem (90 per cent) and ciprofloxacin (99 per cent). Fifty-four (52.8 per cent) Klebsiella and Escherichia coli isolates were determined to be extended-spectrum beta-lactamase (ESBL) producing strains. Antibiotics found to be effective against ESBL-producers were imipenem and ciprofloxacin. The high resistance rate amongst GNB to third-generation cephalosporins is a likely consequence of heavy empirical usage of this group of antibiotics. The carbapenems and quinolones remain useful agents in the management of patients admitted to these units.