Novel antimicrobial strategies to treat multi-drug resistant Staphylococcus aureus infections

Antimicrobial resistance is a major obstacle for the treatment of infectious diseases and currently represents one of the most significant threats to global health. Staphylococcus aureus remains a formidable human pathogen with high mortality rates associated with severe systemic infections. S. aureus has become notorious as a multidrug resistant bacterium, which when combined with its extensive arsenal of virulence factors that exacerbate disease, culminates in an incredibly challenging pathogen to treat clinically. Compounding this major health issue is the lack of antibiotic discovery and development, with only two new classes of antibiotics approved for clinical use in the last 20 years. Combined efforts from the scientific community have reacted to the threat of dwindling treatment options to combat S. aureus disease in several innovative and exciting developments. This review describes current and future antimicrobial strategies aimed at treating staphylococcal colonization and/or disease, examining therapies that show significant promise at the preclinical development stage to approaches that are currently being investigated in clinical trials.     

Antibacterial activity of flavanostilbenes against methicillin-resistant Staphylococcus aureus

Three phytochemical compounds (alopecurone A-C), flavanostilbenes which are produced by condensation between a hydroxyflavanone and a hydroxystilbene, were isolated as major components from the root of Sophora alopecuroides . They uniformly inhibited the growth of 21 strains of methicillin-resistant Staphylococcus aureus with minimum inhibitory concentrations of 3·13–6·25 μg ml^-1.     

Antibacterial activity of flavonoids against methicillin-resistant Staphylococcus aureus strains

An experimental and theoretical study was performed on the anti-staphylococcal activity of 18 natural and synthetic flavonoids against methicillin-resistant Staphylococcus aureus strains. The analysed flavonoids belong to three well-differentiated structural patterns: chalcones, flavanones and flavones. The quantitative analysis of the anti-staphylococcal activity of the compounds was carried out by determining their percent inhibition degree. The hierarchical cluster analysis method was used to analyse the anti-MRSA activity of the compounds. With this methodology, the flavonoids were classified into four groups according to their anti-staphylococcal activity (high, sufficient, intermediate and low). The carbonylic region is of importance because it is part of the bioactive region inducing anti-MRSA activity in the flavonoid molecules. The introduction of OH groups in positions 2' of chalcones and 5 of flavanones (or flavones) increases flavonoid activity, while the OCH(3)groups produce the reverse effect. Using the experimental anti-MRSA activity data of flavonoids and six quantum chemical parameters calculated by means of the AM1 semiempirical molecular orbital method, a very good quantitative structure-activity relationship was obtained (confidence range: 95%; significance level for tests: 0.05; correlation coefficient=0.9842). The selected parameters explain 96.86% of the percent inhibition degree. The obtained relation is consistent with the conclusions formulated in this paper and serves as a theoretical support for some of them. Finally, it is concluded that the flavonoids chalcone, 2'(OH)-chalcone, 2',4'(OH)(2)-chalcone and 2',4(OH)(2)-chalcone might constitute promising therapeutic agents against infections with methicillin-resistant S. aureus strains.     

Potentiation of methicillin activity against methicillin-resistant Staphylococcus aureus by diterpenes

Totarol is a diterpene compound extracted from the totara tree. Totarol and eight other diterpenes were found to potentiate methicillin, one reducing the minimum inhibitory concentration of methicillin against resistant Staphylococcus aureus 256-fold. Totarol did not inhibit the synthesis of DNA or peptidoglycan in S. aureus, but reduced the respiration rate by 70%. Under potentiation conditions, diterpenes had only a slight effect on the respiration rate, but had a significant effect on expression of PBP 2a. We conclude that the primary staphylococcal target for totarol is the respiratory chain, but that potentiation of methicillin by diterpenes is by interference with PBP 2a expression.     

A novel bi-functional chalcone inhibits multi-drug resistant Staphylococcus aureus and potentiates the activity of fluoroquinolones

Staphylococcus aureus is the leading cause of bacteraemia and the dwindling supply of effective antibacterials has exacerbated the problem of managing infections caused by this bacterium. Isoliquiritigenin (ISL) is a plant flavonoid that displays therapeutic potential against S. aureus. The present study identified a novel mannich base derivatives of ISL, IMRG4, active against Vancomycin intermediate S. aureus (VISA). IMRG4 damages the bacterial membranes causing membrane depolarization and permeabilization, as determined by loss of salt tolerance, flow cytometric analysis, propidium idodie and fluorescent microscopy. It reduces the intracellular invasion of HEK-293 cells by S. aureus and decreases the staphylococcal load in different organs of infected mice models. In addition to anti-staphylococcal activity, IMRG4 inhibits the multidrug efflux pump, NorA, which was determined by molecular docking and EtBr efflux assays. In combination, IMRG4 significantly reduces the MIC of norfloxacin for clinical strains of S. aureus including VISA. Development of resistance against IMRG4 alone and in combination with norfloxacin was low and IMRG4 prolongs the post-antibiotic effect of norfloxacin. These virtues combined with the low toxicity of IMRG4, assessed by MTT assay and haemolysis, makes it an ideal candidate to enter drug development pipeline against S. aureus.     

A new actinomycete strain SK4-6 producing secondary metabolite effective against methicillin-resistant Staphylococcus aureus

A new actinomycete strain designated SK4-6, was isolated. This organism exhibited strong activity against bacteria including methicillin-resistant Staphylococcus aureus and Micrococcus luteus, in addition to the causative agents of Candidiasis and Aspergillosis diseases, Candida albicans and Aspergillus species respectively. Morphological and chemical studies indicated that this organism belongs to the genus Streptomyces. Analysis of the 16S rRNA sequence of strain SK4-6 showed a high similarity, 99%, with S. qinlingensis. Optimization of cultural conditions was carried out using Plackett–Burman statistical design where seven variables were examined. Starch, pH and inoculum size showed a positive effect on the production of the active substances, however, sucrose, (NH₄)₂SO₄ and yeast extract repress the production.     

Liposome containing cinnamon oil with antibacterial activity against methicillin-resistant Staphylococcus aureus biofilm

The global burden of bacterial disease remains high and is set against a backdrop of increasing antimicrobial resistance. There is a pressing need for highly effective and natural antibacterial agents. In this work, the anti-biofilm effect of cinnamon oil on methicillin-resistant Staphylococcus aureus was evaluated. Then, cinnamon oil was encapsulated in liposomes to enhance its chemical stability. The anti-biofilm activities of the liposome-encapsulated cinnamon oil against MRSA biofilms on stainless steel, gauze, nylon membrane and non-woven fabrics were evaluated by colony forming unit determination. Scanning electron microscopy and laser scanning confocal microscopy analyses were employed to observe the morphological changes in MRSA biofilms treated with the encapsulated cinnamon oil. As a natural and safe spice, the cinnamon oil exhibited a satisfactory antibacterial performance on MRSA and its biofilms. The application of liposomes further improves the stability of antimicrobial agents and extends the action time.     

Antibacterial activity of chalcones, hydrazones and oxadiazoles against methicillin-resistant Staphylococcus aureus

The increase in antibiotic resistance due to multiple factors has encouraged the search for new compounds which are active against multidrug-resistant pathogens. In this context, chalcones, dihydrochalcones, hydrazones and oxadiazoles were tested against Staphylococcus aureus ATCC 25923 and methicillin-resistant S. aureus (MRSA) isolates, which were obtained from clinical laboratories and were characterized as MRSA using traditional and molecular methods. Among 65 tested compounds, two chalcones, one dihydrochalcone and two hydrazones were active against MRSA. Based on the minimal inhibitory concentration and cytotoxicity, hydrazones provided a better selectivity index than chalcones. Active hydrazones are promising antibiotic-like substances and they should be the subject of further microbiological studies.     

Antibacterial activity of aminoderivatized chitosans against methicillin-resistant Staphylococcus aureus (MRSA)

This work describes the anti-MRSA activity of aminoderivatized chitosans. Two kinds of aminoethyl-chitosans (AEC), AEC90 and AEC50, having degrees of deacetylation of 90% and 50%, respectively, exhibited the strongest anti-MRSA activities by presenting MICs of 16–64 μg/mL against two standard strains and twelve clinical isolates. The bactericidal activity, thermal and pH stability, and cell membrane integrity effects of AEC90 and AEC50 are also discussed.     

Antibacterial activity of isoflavonoids isolated from Erythrina variegata against methicillin-resistant Staphylococcus aureus

AIMS: To screen 16 isoflavonoids isolated from Erythrina variegata (Leguminosae) for their antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA). METHODS AND RESULTS: The roots of E. variegata were macerated with acetone. The chloroform-soluble fraction of the residue was subjected to repeated silica gel column chromatography followed by elution with various solvents. Structures of the isolated compounds were determined by extensive spectroscopic studies. Each compound was dissolved in dimethyl sulphoxide and added to agar plates (final concentration 1.56-100 microg ml(-1) and suspensions of MRSA spotted onto the agar plates to determine the minimum inhibitory concentration (MIC). Repeated silica gel chromatography yielded 16 compounds and spectroscopic studies revealed that all were isoflavonoids. Whilst 14 compounds showed antibacterial activity in this concentration range, the MIC values varied significantly among them. Of the active compounds, 3,9-dihydroxy-2,10-di(gamma,gamma-dimethylallyl)-6a,11a-dehydropterocarpan (erycristagallin) and 9-hydroxy-3-methoxy-2-gamma,gamma-dimethylallylpterocarpan (orientanol B) exhibited the highest activity with MIC values of 3.13-6.25 microg ml(-1). CONCLUSIONS: Erycristagallin and orientanol B showed the highest anti-MRSA activity (3.13-6.25 microg ml(-1). SIGNIFICANCE AND IMPACT OF THE STUDY: Erycristagallin and orientanol B could be leading compounds for phytotherapeutic agents against MRSA infections.     

Anti-biofilm activity of Quercus infectoria G. Olivier against methicillin-resistant Staphylococcus aureus

Aims: To establish the effect of Quercus infectoria G. Olivier extract and its main constituent, tannic acid, on staphylococcal biofilm and their anti‐biofilm mechanisms. Methods and Results: Anti‐biofilm activity of the plant materials on clinical isolated of methicillin‐resistant Staphylococcus aureus and methicillin‐susceptible Staph. aureus was employed using a crystal violet‐stained microtiter plate method. The extract at minimum inhibitory concentration (MIC; 0·25 mg ml^?1) was significantly reduced the biofilm formation of the isolates (P < 0·05). The effect on staphylococcal cell surface hydrophobicity (CSH) of the test compounds was investigated as a possible mode of action of the anti‐biofilm activity. The hydrophobicity index of all the bacterial isolates increased following treatment with supra‐MIC, MIC and sub‐MIC of the extract and tannic acid. Observation of the treated bacterial cells by electron microscopy revealed that the test compounds caused clumps of partly divided cocci with thickened and slightly rough cell wall. Conclusions: The results indicated that Q. infectoria extract and tannic acid affected staphylococcal biofilm formation and their effect on bacterial CSH and cell wall may involve in the anti‐biofilm activity. Significance and Impact of the Study: This evidence highlighted the anti‐biofilm potency of the natural products and clarified their anti‐biofilm mechanisms.     

铜绿假单胞菌抗菌物质对耐甲氧西林金黄色葡萄球菌的抑菌活性研究

目的观察铜绿假单胞菌抗菌物质对耐甲氧西林金黄色葡萄球菌(methicillin-resistant Staphylococcusaureus,MRSA)的体外抑菌活性。方法用交叉划线接种方法进行铜绿假单胞菌对32株耐甲氧西林金葡菌的体外抗菌活性的测定。结果铜绿假单胞菌抗菌物质对MRSA的体外抑菌活性良好,产生色素的菌株的抗菌活性最好,15株铜绿假单胞菌中,7株产蓝绿色色素的铜绿假单胞菌,对MRSA的抑制率均达到了100%,平均抑菌带的宽度为37.7 mm。结论铜绿假单胞菌抗菌物质对32株MRSA具有较强的抗菌活性,无疑对MRSA感染的抗菌药物研制方面开辟了一条新的途径。这是国内的首次研究报道。     

In vitro activity of the antimicrobial peptide AP7121 against the human methicillin-resistant biofilm producers Staphylococcus aureus and Staphylococcus epidermidis

Abstract

In vitro activity against methicillin-resistant Staphylococcus aureus (MRSA) and Staphylococcus epidermidis biofilm producers from blood cultures of patients with prosthetic hip infections was evaluated. The Minimum Inhibitory Concentration (MIC) for AP7121 was determined and the bactericidal activity of AP7121 (MICx1, MICx4) against planktonic cells was studied at 4, 8 and 24?h. The biofilms formed were incubated with AP7121 (MICx1, MICx4) for 1 and 24?h. The anti-adhesion effect of an AP7121-treated inert surface over the highest MIC isolate was studied with scanning electron microscopy (SEM). The bactericidal activity of AP7121 against all the planktonic staphylococcal cells was observed at 4?h at both peptide concentrations. Dose-dependent anti-biofilm activity was detected. AP7121 (MICx4) showed bactericidal activity at 24?h in all isolates. SEM confirmed prevention of biofilm formation. This research showed the in vitro anti-biofilm activity of AP7121 against MRSA and S. epidermidis and the prevention of biofilm formation by them on an abiotic surface.     

Effect of Saliva miltiorrhiza bunge on antimicrobial activity and resistant gene regulation against methicillin-resistant Staphylococcus aureus (MRSA)

This study was conducted in an effort to evaluate the antimicrobial activity and antibiotic-resistant gene regulation from Saliva miltiorrhiza Bunge on methicillin-resistant Staphylococcus aureus (MRSA). A variety of solvent fractions and methanol extracts of S. miltiorrhiza Bunge were tested in order to determine its antimicrobial activities against S. aureus and MRSA. As a result, the hexane fraction of S. miltiorrhiza Bunge evidenced the highest levels of antimicrobial activity against S. aureus and MRSA. The MICs of the hexane fraction against various MRSA specimens were 64相似文献   

大黄酸抗耐甲氧西林金黄色葡萄球菌的抗菌机制

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In vitro antimicrobial activity of pannarin alone and in combination with antibiotics against methicillin-resistant Staphylococcus aureus clinical isolates

The in vitro antimicrobial activities of pannarin, a depsidone isolated from lichens, collected in several Southern regions of Chile (including Antarctica), was evaluated alone and in combination with five therapeutically available antibiotics, using checkerboard microdilution assay against methicillin-resistant clinical isolates strains of Staphylococcus aureus. MIC(90), MIC(50), as well as MBC(90) and MBC(50), were evaluated. A moderate synergistic action was observed in combination with gentamicin, whilst antagonism was observed in combination with levofloxacin. All combinations with erythromycin were indifferent, whilst variability was observed for clindamycin and oxacillin combinations. Data from checkerboard assay were analysed and interpreted using the fractional inhibitory concentration index and the response surface approach using the ΔE model. Discrepancies were found between both methods for some combinations. In order to asses cellular lysis after exposure to pannarin, cell membrane permeability assay was performed. The treatment with pannarin produces bactericidal activity without significant calcein release, consistent with lack of lysis or even significant structural damage to the cytoplasmic membrane. Furthermore, pannarin shows low hemolytic activity and moderate cytotoxic effect on peripheral blood mononuclear cells. These findings suggest that the natural compound pannarin might be a good candidate for the individualization of novel templates for the development of new antimicrobial agents or combinations of drugs for chemotherapy.