naphthoquinones and Staphylococcal-Infections

1, 4-naphthoquinone, a plant-based quinone derivative, has gained much attention for its effectiveness against several biofilm-linked diseases. The biofilm inhibitory effect of 1, 4-naphthoquinone against Staphylococcus aureus has already been reported in our previous study. We observed that the extracellular DNA (eDNA) could play an important role in holding the structural integrity of the biofilm. Hence, in this study, efforts have been directed to examine the possible interactions between 1, 4-naphthoquinone and DNA. An in silico analysis indicated that 1, 4-naphthoquinone could interact with DNA through intercalation. To validate the same, UV-Vis spectrophotometric analysis was performed in which a hypochromic shift was observed when the said molecule was titrated with calf-thymus DNA (CT-DNA). Thermal denaturation studies revealed a change of 8℃ in the melting temperature (Tm) of CT-DNA when complexed with 1, 4-naphthoquinone. The isothermal calorimetric titration (ITC) assay revealed a spontaneous intercalation between CT-DNA and 1, 4-naphthoquinone with a binding constant of 0.95 ± 0.12 × 10

Topics: Biofilms; DNA; Ethidium; Humans; Naphthoquinones; Staphylococcal Infections; Staphylococcus aureus

Topics: Anti-Bacterial Agents; beta-Lactams; Drug Resistance, Multiple, Bacterial; Drug Synergism; Humans; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Naphthoquinones; Staphylococcal Infections

Staphylococcus aureus, a Gram-positive opportunistic microorganism, promotes pathogenicity in the human host through biofilm formation. Microorganisms associated with biofilm often exhibit drug-resistance property that poses a major threat to public healthcare. Thus, the exploration of new therapeutic approaches is the need of the hour to manage biofilm-borne infections. In the present study, efforts are put together to test the antimicrobial as well as antibiofilm activity of 1,4-naphthoquinone against Staphylococcus aureus. The result showed that the minimum bactericidal concentration (MBC) of this compound was found to be 100 µg/mL against Staphylococcus aureus. In this regard, an array of experiments (crystal violet, biofilm protein measurement, and microscopic analysis) related to biofilm assay were conducted with the sub-MBC concentrations (1/20 and 1/10 MBC) of 1,4-naphthoquinone. All the results of biofilm assay demonstrated that these tested concentrations (1/20 and 1/10 MBC) of the compound (1,4-naphthoquinone) showed a significant reduction in biofilm development by Staphylococcus aureus. Moreover, the tested concentrations (1/20 and 1/10 MBC) of the compound (1,4-naphthoquinone) were able to reduce the microbial motility of Staphylococcus aureus that might affect the development of biofilm. Further studies revealed that the treatment of 1,4-naphthoquinone to the organism was found to increase the cellular accumulation of reactive oxygen species (ROS) that resulted in the inhibition of biofilm formation by Staphylococcus aureus. Hence, it can be concluded that 1,4-naphthoquinone might be considered as a promising compound towards biofilm inhibition caused by Staphylococcus aureus.

Topics: Anti-Bacterial Agents; Biofilms; Humans; Microbial Sensitivity Tests; Naphthoquinones; Reactive Oxygen Species; Staphylococcal Infections; Staphylococcus aureus

Topics: Animals; Anti-Bacterial Agents; Bacterial Proteins; beta-Lactamase Inhibitors; beta-Lactamases; Disease Models, Animal; Humans; Kinetics; Molecular Docking Simulation; Naphthoquinones; Staphylococcal Infections; Staphylococcus aureus; Streptomyces

Staphylococcus aureus causes several nosocomial and community-acquired infections in human host involving biofilm. Thus, strategies need to be explored to curb biofilm threats by either inhibiting the formation of biofilm or disintegrating the pre-existing biofilm. Towards this direction, we had already revealed the biofilm inhibiting properties of 1,4-naphthoquinone against S. aureus. In this study, we have investigated whether this compound can act on pre-existing biofilm. Hence, biofilm of S. aureus was developed first and challenged further with 1,4-naphthoquinone. Experiments such as crystal violet assay, fluorescence microscopy, and estimation of total biofilm protein were performed to confirm the biofilm disintegration properties of 1,4-naphthoquinone. The disintegration of pre-existing biofilm could be attributed to the generation of reactive oxygen species (ROS). To investigate further, we observed that extracellular DNA (eDNA) was found to play an important role in holding the biofilm network as DNaseI treatment could cause an efficient disintegration of the same. To examine the effect of ROS on the eDNA, we exposed pre-existing biofilm to either 1,4-naphthoquinone or a combination of both 1,4-naphthoquinone and ascorbic acid for different length of time. Post-incubation, ROS generation and the amount of eDNA associated with the biofilm were determined wherein an inversely proportional relationship was observed between them. The result indicated that with the increase of ROS generation, the amount of eDNA associated with biofilm got decreased substantially. Thus, the results indicated that the generation of ROS could degrade the eDNA thereby compromising the integrity of biofilm which lead to the disintegration of pre-existing biofilm.

Topics: Biofilms; Humans; Naphthoquinones; Reactive Oxygen Species; Staphylococcal Infections; Staphylococcus aureus

α-Mangostin-rich extract (AME) exhibited satisfactory inhibitory activities against all tested MRSA strains, with minimum inhibitory concentrations (MICs) of 7·8-31·25 µg ml

Topics: Ampicillin; Anti-Bacterial Agents; Drug Synergism; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Naphthoquinones; Plant Extracts; Staphylococcal Infections; Xanthones

The treatment of Staphylococcus aureus (S. aureus) infections has become more difficult due to the emergence of multidrug resistance in the bacteria. Here, we report the synthesis of a lawsone (2-hydroxy-1,4-naphthoquinone)-based compound as an antimicrobial agent against methicillin-resistant S. aureus (MRSA). A series of lawsone-derivative compounds were synthesized by means of tuning the lipophilicity of lawsone and screened for minimum inhibitory concentrations against MRSA to identify a candidate compound that possesses a potent antibacterial activity. The identified lawsone-derivative compound exhibited significantly improved drug resistance profiles against MRSA compared to conventional antibiotics. The therapeutic efficacy of the compound was validated using murine models of wound infection as well as non-lethal systemic infection induced by MRSA. Our study further revealed the multifaceted modes of action of the compound, mediated by three distinctive mechanisms: (1) cell membrane damage, (2) chelation of intracellular iron ions, and (3) generation of intracellular reactive oxygen species.

Topics: Animals; Anti-Bacterial Agents; Bacterial Outer Membrane; Male; Methicillin-Resistant Staphylococcus aureus; Mice; Mice, Inbred C57BL; Microbial Sensitivity Tests; Naphthoquinones; Staphylococcal Infections

Despite the existing antibiotics, antimicrobial resistance is a major challenge. Consequently, the development of new drugs remains in great demand. Quinones is part of a broad group of molecules that present antibacterial activity besides other biological properties. The main purpose of this study was to evaluate the antibiofilm activities of synthetic N,O-acetals derived from 2-amino-1,4-naphthoquinone [7a: 2-(methoxymethyl)-amino-1,4-naphthoquinone; 7b: 2-(ethoxymethyl)-amino-1,4-naphthoquinone; and 7c: 2-(propynyloxymethyl)-amino-1,4-naphthoquinone] against methicillin-resistant Staphylococcus aureus (MRSA). The derivatives 7b and 7c, specially 7b, caused strong impact on biofilm accumulation. This inhibition was linked to decreased expression of the genes fnbA, spa, hla and psmα3. More importantly, this downregulation was paralleled by the modulation of global virulence regulators. The substitution of 2-ethoxymethyl (7b) in comparison with 2-propynyloxymethyl (7c) enhanced sarA-agr inhibition, decreased fnbA transcripts (positively regulated by sarA) and strongly impaired biofilm accumulation. Indeed, 7b triggered intensive autolysis and was able to eliminate vancomycin-persistent cells. Consequently, 7b is a promising molecule displaying not only antimicrobial effects, but also antibiofilm and antipersistence activities. Therefore, 7b is a good candidate for further studies involving the development of novel and more rational antimicrobials able to act in chronic and recalcitrant infections, associated with biofilm formation.

Topics: Acetals; Animals; Anti-Bacterial Agents; Bacterial Proteins; Biofilms; Cell Line; Chlorocebus aethiops; Down-Regulation; Drug Resistance, Bacterial; Hemolysis; Humans; Materials Testing; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Naphthoquinones; Staphylococcal Infections; Vero Cells; Virulence

Topics: Animals; Anti-Bacterial Agents; Boraginaceae; Drug Synergism; Mice; Microbial Sensitivity Tests; Naphthoquinones; Pentanoic Acids; Peritonitis; Sepsis; Staphylococcal Infections; Staphylococcus aureus

In this study, chitosan/bioactive glass (BG)/lawsone coatings were deposited by electrophoretic deposition (EPD) on polyetheretherketone (PEEK)/BG layers (previously deposited by EPD on 316-L stainless steel) to produce bioactive and antibacterial coatings. First, the EPD of chitosan/BG/lawsone was optimized on stainless steel in terms of suspension stability, homogeneity and thickness of coatings. Subsequently, the optimized EPD parameters were used to produce bioresorbable chitosan/bioactive glass (BG)/lawsone coatings on PEEK/BG layers. The produced layered coatings were characterized in terms of composition, microstructure, corrosion resistance, in vitro bioactivity, drug release kinetics and antibacterial activity. Ultraviolet/Visible (UV/VIS) spectroscopic analyses confirmed the release of lawsone from the coatings. Moreover, the deposition of chitosan/BG coatings was confirmed by Scanning Electron Microscopy (SEM) and Fourier Transform Infrared spectroscopy (FTIR). The coated specimens presented higher corrosion resistance (10 times) in comparison to that of bare 316-L stainless steel and showed convenient wettability for initial protein attachment. The presence of lawsone in the top layer provided antibacterial effects against Staphylococcus carnosus. Moreover, the developed coatings formed apatite-like crystals upon immersion in simulated body fluid, indicating the possibility of achieving close interaction between the coating surface and bone. © 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A: 3111-3122, 2018.

Topics: Anti-Bacterial Agents; Benzophenones; Chitosan; Coated Materials, Biocompatible; Drug Delivery Systems; Drug Liberation; Humans; Ketones; Naphthoquinones; Polyethylene Glycols; Polymers; Staphylococcal Infections; Staphylococcus; Wettability

Naphtho[1,2-b]furan-4,5-dione (N12D) and naphtho[2,3-b]furan-4,9-dione (N23D) are furanonaphthoquinone derivatives from natural resources. We examined the antimicrobial activity of N12D and N23D against drug-resistant Staphylococcus aureus.. Minimum inhibitory concentration, minimum bactericidal concentration, bacterial viability and agar diffusion assay were conducted against methicillin-resistant S. aureus (MRSA) and clinical isolates of vancomycin-resistant S. aureus.. The minimum inhibitory concentration of N12D and N23D against MRSA was 4.9-9.8 and 39 μM, respectively. With regard to the agar diffusion test, the inhibition zone of the quinone compounds was threefold larger than that of oxacillin. N12D was found to inhibit MRSA biofilm thickness from 24 to 16 μm as observed by confocal microscopy. N12D showed a significant reduction of the intracellular MRSA burden without decreasing the macrophage viability. The antibacterial mechanisms of N12D may be bacterial wall/membrane damage and disturbance of gluconeogenesis and the tricarboxylic acid cycle.

Topics: Anti-Bacterial Agents; Bacterial Proteins; Biofilms; Cell Membrane; Cell Survival; Citric Acid Cycle; Furans; Gluconeogenesis; Humans; Keratinocytes; Macrophages; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Microbial Viability; Microscopy, Electron, Transmission; Molecular Docking Simulation; Naphthoquinones; Neutrophils; Oxacillin; Proteomics; Pseudomonas aeruginosa; Staphylococcal Infections; Staphylococcus aureus; Vancomycin Resistance

Candida albicans and Staphylococcus aureus are opportunistic pathogens. Despite causing a number of independent infections, both pathogens can co-infect to cause urinary tract infections, skin infections, biofilm associated infections, sepsis and pneumonia. Infections of these two pathogens especially their biofilm associated infections are often difficult to treat using currently available anti-bacterial and anti-fungal agents. In order to identify a common anti-microbial agent which could confer a broad range of protection against their infections, we screened several phytochemicals and identified plumbagin (5-hydroxy-2-methyl-1,4-naphthoquinone), a phytochemical from Plumbago species as a potent antimicrobial agent against S. aureus and C. albicans, with a minimum inhibitory concentration of 5μg/ml. Antimicrobial activity of plumbagin was validated using an ex-vivo porcine skin model. For better understanding of the antimicrobial activity of plumbagin, a Drosophila melanogaster infection model was used, where D. melanogaster was infected using S. aureus and C. albicans, or with both organisms. The fly's survival rate was dramatically increased when infected flies were treated using plumbagin. Further, plumbagin was effective in preventing and dispersing catheter associated biofilms formed by these pathogens. The overall results of this work provides evidence that plumbagin, possesses an excellent antimicrobial activity which should be explored further for the treatment of S. aureus and C. albicans infections.

Topics: Animals; Anti-Infective Agents; Biofilms; Candida albicans; Candidiasis; Disease Models, Animal; Drosophila melanogaster; Female; Microbial Sensitivity Tests; Naphthoquinones; Phytochemicals; Plumbaginaceae; Staphylococcal Infections; Staphylococcus aureus; Survival Analysis; Treatment Outcome

Juglone is a plant-derived 1,4-naphthoquinone with confirmed antibacterial activity. However, the mechanism of action of juglone against Staphylococcus aureus remains unclear. Possible mechanisms were explored by a proteomic analysis of S. aureus proteins that are inhibited by juglone. Two-dimensional gel electrophoresis revealed that 21 protein spots were differentially expressed between juglone-treated and untreated cells of which 13 were identified. A bioinformatic analysis revealed that proteins participating in protein synthesis, the tricarboxylic acid cycle, as well as DNA and RNA synthesis were inhibited by juglone, thus leading to cell collapse. These findings provide clues regarding the mechanism of action of juglone, which can be effective for treating cases of S. aureus infection.

Topics: Anti-Bacterial Agents; Bacterial Proteins; Electrophoresis, Gel, Two-Dimensional; Humans; Naphthoquinones; Proteomics; Staphylococcal Infections; Staphylococcus aureus

The aim of this study was to evaluate the antimicrobial activity of lapachol, α-lapachone, β-lapachone and six antimicrobials (ampicillin, amoxicillin/clavulanic acid, cefoxitin, gentamicin, ciprofloxacin and meropenem) against twelve strains of Staphylococcus aureus from which resistance phenotypes were previously determined by the disk diffusion method. Five S. aureus strains (LFBM 01, LFBM 26, LFBM 28, LFBM 31 and LFBM 33) showed resistance to all antimicrobial agents tested and were selected for the study of the interaction between β-lapachone and antimicrobial agents, busing checkerboard method. The criteria used to evaluate the synergistic activity were defined by the Fractional Inhibitory Concentration Index (FICI). Among the naphthoquinones, β-lapachone was the most effective against S. aureus strains. FICI values ranged from 0.07 to 0.5, suggesting a synergistic interaction against multidrug resistant S. aureus (MRSA) strains. An additive effect was observed with the combination β-lapachone/ciprofloxacin against the LFBM 33 strain. The combination of β-lapachone with cefoxitin showed no added benefit against LFBM 31 and LFBM 33 strains. This study demonstrated that, in general, β-lapachone combined with beta lactams antimicrobials, fluoroquinolones and carbapenems acts synergistically inhibiting MRSA strains.

Topics: Anti-Bacterial Agents; Ciprofloxacin; Drug Combinations; Drug Synergism; Humans; Methicillin Resistance; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Naphthoquinones; Staphylococcal Infections; Tabebuia

Topics: Electrophoresis, Agar Gel; Humans; Naphthoquinones; Plants, Medicinal; Plasmids; Staphylococcal Infections; Staphylococcus aureus; Vancomycin Resistance

For the systematic SAR study on mansonone F, a series of C6 and C9 analogs of mansonone F have been synthesized and their anti-MRSA activities were evaluated. Most of the analogs exhibited good or excellent anti-MRSA activities. In particular, the 6-n-butylmansonone F showed fourfold higher antibacterial activities compared to that of vancomycin.

Topics: Anti-Infective Agents; Drug Resistance, Bacterial; Methicillin; Models, Chemical; Naphthoquinones; Quinones; Sesquiterpenes; Staphylococcal Infections; Staphylococcus aureus; Structure-Activity Relationship; Vancomycin

Fourteen extracts from Brazilian traditional medicinal plants used to treat infectious diseases were used to look for potential antimicrobial activity against multiresistant bacteria of medical importance. Staphylococcus aureus strains were susceptible to extracts of Punica granatum and Tabebuia avellanedae. The minimum inhibitory concentrations (MICs) of the total extracts and of additional fractions of these plants were determined by employing strains of methicillin-resistant (MRSA) and -sensitive (MSSA) S. aureus, including isolates of the PFGE clone A, which is prevalent in Brazil and two ATCC reference strains. A mixture of ellagitannins isolated from P. granatum and two naphthoquinones isolated from T. avellanedae demonstrated antibacterial activity against all S. aureus strains tested. Semi-synthetic furanonaphthoquinones (FNQs) showed lower MICs than those exhibited by natural occurring naphthoquinones. The results indicate that these natural products can be effective potential candidates for the development of new strategies to treat MRSA infections.

Topics: Brazil; Humans; Hydrolyzable Tannins; In Vitro Techniques; Lythraceae; Methicillin Resistance; Microbial Sensitivity Tests; Naphthoquinones; Phytotherapy; Plant Extracts; Plants, Medicinal; Staphylococcal Infections; Staphylococcus aureus; Tabebuia; Tannins

The antibiotic activity of new synthetic isoxazolylnaphthoquinone imines was studied. Pseudomonas aeruginosa ATCC 27853 and Escherichia coli ATCC 25922 were resistant to the four compounds studied (MIC > 128 micrograms ml-1), but Staphylococcus aureus ATCC 25923, ATCC 29213 and 30 clinical isolates of Staph. aureus were inhibited by 2-hydroxy-N-(3,4-dimethyl-5-isoxazolyl)-1,4-naphthoquinone-4-imine (I). This compound diminished bloodstream infection of mice injected i.m. with Staph. aureus; septicaemia decayed significantly when I was applied at the beginning of the infection while when I was given 3 d after bacterial challenge, a significant protection was afforded. Bactericidal activity in serum increased during the 5 h after I was administered i.p. The acetyl derivative of I had a high MIC but when inoculated orally in mice decreased the Staph. aureus counts in circulation. This protection occurred only when the schedule of administration started close to the bacterial challenge. Antibiotic activity in vivo may be associated with in vitro effects.

Topics: Animals; Anti-Infective Agents; Female; Isoxazoles; Male; Mice; Mice, Inbred BALB C; Microbial Sensitivity Tests; Molecular Structure; Naphthols; Naphthoquinones; Staphylococcal Infections

New semi-naphthaquinone antibiotics A80915A, B, C, and D were isolated from the fermented broth of Streptomyces aculeolatus A80915 (NRRL 18422). Factors A and C, present in both the broth filtrate and mycelial methanol extract, and factors B and D, found predominantly in the broth filtrate, were recovered by extraction with ethyl acetate. Purification of the individual factors was accomplished by preparative reverse phase high performance liquid chromatograph on C18 bonded silica supports. Factors A through D show antimicrobial activity against Gram-positive aerobic and anaerobic organisms in vitro. Mechanism of action studies demonstrated nearly complete inhibition of macromolecular biosynthesis (protein, RNA, DNA, and cell wall) by A80915 factors A through D. A less highly cyclized semi-naphthaquinone, A80915 factor G, was isolated from the broth of the strain fermented in an alternate medium.

Topics: Animals; Anti-Bacterial Agents; Bacteria; Bacterial Proteins; Chromatography, High Pressure Liquid; DNA, Bacterial; Fermentation; Mice; Microscopy, Electron, Scanning; Molecular Structure; Naphthoquinones; RNA, Bacterial; Soil Microbiology; Staphylococcal Infections; Streptococcal Infections; Streptomyces

The six major components of M-92, a new antibiotic complex produced by Micromonospora verruculosa MCRL 0404 showed a similar type of antimicrobial spectrum. Among these components, VA-2 exhibited the most potent antimicrobial activity, particularly significantly against some Gram-positive bacteria and Neisseria. VA-2 and BN-1 also exhibited marked inhibitory effects against L-forms of Staphylococcus aureus 209P and Mycoplasma. The MICs of VA-2, BA-4 and BN-1 were remarkably affected by the pH of the test medium, the inoculum size and the amount of horse serum added in the medium. By intraperitoneal administration, these components showed good protective effects in mice infected intraperitoneally with Staphylococcus aureus Smith. However, the protective effect decreased remarkably by other administration routes. In addition, components such as VA-2 and BN-1 exhibited cytotoxicity against HeLa S-3 cells in vitro and excellent in vivo antitumor activity against Ehrlich carcinoma. VA-2 possessed a high order of acute toxicity to mice [LD50:1.9 mg/kg (i.p.); 1.8 mg/kg (i.v.)], but others were relatively less toxic.

Topics: Animals; Anti-Bacterial Agents; Antibiotics, Antineoplastic; Bacteria; Carcinoma, Ehrlich Tumor; Female; HeLa Cells; Humans; Lethal Dose 50; Male; Mice; Mice, Inbred ICR; Micromonospora; Mycoplasma; Naphthoquinones; Neisseria; Staphylococcal Infections