Potent in vitro methicillin-resistant Staphylococcus aureus activity of 2-(1H-indol-3-yl)quinoline derivatives

A novel structural class of antibacterials, 2-(1H-indol-3-yl)quinolines, effective against methicillin-resistant Staphylococcus aureus (MRSA), was discovered from a combinatorial library. A structure-activity relationship (SAR) study was conducted to determine the pharmacophore and increase the potency of these compounds. Compounds were prepared that had minimum inhibitory concentrations (MICs) < 1.0 microg/mL against MRSA and retained activity against two strains of glycopeptide intermediate-resistant S. aureus (GISA).     

Synergistic effects between aminoethyl-chitosans and β-lactams against methicillin-resistant Staphylococcus aureus (MRSA)

Two kinds of aminoethyl-chitosans (AEC), AEC90 and AEC50, which had degrees of deacetylation of 90% and 50%, respectively, were prepared and their synergistic effects in combination with β-lactams including ampicillin, penicillin, and oxacillin against two standard methicillin-resistant Staphylococcus aureus (MRSA) strains and twelve clinical isolated MRSA strains were investigated. When AECs and β-lactams were combined, synergistic effects were observed with fractional inhibitory concentration (FIC) indices of 0.252–0.508, and the MICs of β-lactams in the presence of AECs were dramatically reduced.     

An extract from teak (Tectona grandis) bark inhibited Listeria monocytogenes and methicillin resistant Staphylococcus aureus

AIMS: The aim of this study was to characterize the inhibitory mechanism in teak (Tectona grandis) bark and to determine its effectiveness against Listeria monocytogenes and methicillin resistant Staphylococcus aureus (MRSA). METHODS AND RESULTS: Methanol extracts of teak bark were inhibitory to L. monocytogenes and MRSA by means of disc diffusion. Gas chromatography-mass spectrometry, and (1)H and (13)C nuclear mass resonance analyses revealed that the inhibitory compound had a molecular weight of 174, and a structure of 5-hydroxy-1,4-naphthalenedione (Juglone). CONCLUSIONS: 5-hydroxy-1,4-naphthalenedione (Juglone) inhibited L. monocytogenes and MRSA. SIGNIFICANCE AND IMPACT OF THE STUDY: A compound in an extract of teak bark was inhibitory to L. monocytogenes and MRSA.     

Synergistic effect between dieckol from <Emphasis Type="Italic">Ecklonia stolonifera</Emphasis> and β-lactams against methicillin-resistant <Emphasis Type="Italic">Staphylococcus aureus</Emphasis>

We have been attempting for some time to discover a compound evidencing antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA). The dieckol isolated from Ecklonia stolonifera has been shown to exhibit antibacterial activity against methicillin-susceptible S. aureus (MSSA) and MRSA. The minimum inhibitory concentrations (MICs) of dieckol were determined in a range of 32 to 64 μg/mL against standard MSSA and MRSA strains. Furthermore, dieckol clearly reversed the high-level ampicillin and penicillin resistance of MRSA. The MICs of ampicillin against two standard strains of MRSA were dramatically reduced from 512 to 0.5 μg/mL in combination with 1/4 MIC of dieckol (16 μg/mL). The fractional inhibitory concentration (FIC) indices of ampicillin and penicillin were measured from 0.066 to 0.266 in combination with 8 or 16 μg/mL of dieckol against all tested MRSA strains, thereby suggesting that dieckol-ampicillin or dieckol-penicillin combinations exert a synergistic effect against MRSA. The results of this study indicate that dieckol, administered in combination with β-lactams, may prove effective in the treatment of MRSA infections. Our finding may also contribute to the development of an alternative phytotherapeutic anti-MRSA agent.     

Impact of rapid screening tests on acquisition of meticillin resistant Staphylococcus aureus: cluster randomised crossover trial

Objective To determine whether introducing a rapid test for meticillin resistant Staphylococcus aureus (MRSA) screening leads to a reduction in MRSA acquisition on hospital general wards.Design Cluster randomised crossover trial.Setting Medical, surgical, elderly care, and oncology wards of a London teaching hospital on two sites.Main outcome measure MRSA acquisition rate (proportion of patients negative for MRSA who became MRSA positive).Participants All patients admitted to the study wards who were MRSA negative on admission and screened for MRSA on discharge.Intervention Rapid polymerase chain reaction based screening test for MRSA compared with conventional culture.Results Of 9608 patients admitted to study wards, 8374 met entry criteria and 6888 had full data (82.3%); 3335 in the control arm and 3553 in the rapid test arm. The overall MRSA carriage rate on admission was 6.7%. Rapid tests led to a reduction in median reporting time from admission, from 46 to 22 hours (P<0.001). Rapid testing also reduced the number of inappropriate pre-emptive isolation days between the control and intervention arms (399 v 277, P<0.001). This was not seen in other measurements of resource use. MRSA was acquired by 108 (3.2%) patients in the control arm and 99 (2.8%) in the intervention arm. When predefined confounding factors were taken into account the adjusted odds ratio was 0.91 (95% confidence interval 0.61 to 1.234). Rates of MRSA transmission, wound infection, and bacteraemia were not statistically different between the two arms.Conclusion A rapid test for MRSA led to the quick receipt of results and had an impact on bed usage. No evidence was found of a significant reduction in MRSA acquisition and on these data it is unlikely that the increased costs of rapid tests can be justified compared with alternative control measures against MRSA.Trial registration Clinical controlled trials ISRCTN75590122.     

Remarkable synergies between baicalein and tetracycline, and baicalein and beta-lactams against methicillin-resistant Staphylococcus aureus

During the screening of compounds that potentiate the effect of antimicrobial agents against methicillin-resistant Staphylococcus aureus(MRSA), we found that an extract of thyme (Thymus vulgaris L) leaves greatly reduced the minimum inhibitory concentration (MIC) of tetracycline against MRSA. We isolated the effective compound and identified it as baicalein (5, 6, 7-trihydroxyflavone). One of the clinically isolated MRSA strains possessed tetK, a gene encoding active efflux pump for tetracycline. We examined the effect of baicalein on the efflux of tetracycline, using Escherichia coli KAM32/pTZ1252 carrying the tetK. The E. coli KAM32/pTZ1252 showed 8 to 16 times higher MIC than E. coli KAM32. We observed strong inhibition of transport of tetracycline by baicalein with membrane vesicles prepared from E. coli KAM32/pTZ1252. Baicalein also showed synergy with tetracycline in a MRSA strain that doesn't possess tetK, or with beta-lactams. Thus, mechanisms of the synergies seem to be versatile.     

A new class of anti-MRSA and anti-VRE agents: preparation and antibacterial activities of indole-containing compounds

A new class of indole-containing compounds were prepared by the use of three component reaction and their in vitro antibacterial activities (MIC) were evaluated against Staphylococcus aureus and Enterococcus faecium including MRSA and VRE.     

Synergistic interactions between artocarpin-rich extract,lawsone methyl ether and ampicillin on anti-MRSA and their antibiofilm formation

Artocarpin-rich extract (ARE) was prepared using a green technology and standardized to contain 49·6% w/w artocarpin, while lawsone methyl ether was prepared using a green semi-synthesis. ARE, LME and ampicillin exhibited weak anti-MRSA activity with the MICs of 31·2–62·5 µg/ml. Based on the checkerboard assay, the synergistic interaction between ARE (0·03 µg/ml) and LME (0·49 µg/ml) against four MRSA isolates were observed with the fractional inhibitory concentration index (FICI) value of 0·008, while those of ARE (1·95–7·81 µg/ml) and ampicillin (0·49 µg/ml) as well as LME (0·49–1·95 µg/ml) and ampicillin (0·49 µg/ml) were 0·016–0·257. The time kill confirmed the synergistic interactions against MRSA with different degrees. The combination of ARE and LME as well as its combinations with ampicillin altered the membrane permeability of MRSA, which led to release of the intracellular materials. In addition, each compound inhibited the biofilm formation of standard MRSA (DMST 20654) and the clinical isolate (MRSA 1096). These findings suggested that cocktails containing ARE and LME might be used to overcome problems associated with MRSA. Additionally, the results implied that combination of either ARE or LME with available conventional antibiotic agents might be effective in countering these perilous pathogens.     

Changes in antibiotic susceptibility in staphylococci habituated to sub-lethal concentrations of tea tree oil (Melaleuca alternifolia)

Aims: To investigate the effect of sub‐lethal challenge with tea tree oil (TTO) on the antibiotic resistance profiles of staphylococci. Methods and Results: Isolates of methicillin‐resistant/‐sensitive Staphylococcus aureus (MRSA and MSSA) and coagulase‐negative staphylococci (CoNS) were habituated to sub‐lethal concentrations of TTO (72 h). Following habituation, the minimum inhibitory concentrations (MIC) of antibiotics and TTO were determined. Habituated MRSA/MSSA cultures had higher (P < 0·05) MIC values than control cultures for the examined antibiotics. Habituated MRSA/MSSA cultures also displayed decreased susceptibility to TTO. Although the MIC of habituated MRSA/MSSA for the examined antibiotics reverted to control values after subsequent culture in the absence of TTO, the increased MIC against TTO were maintained. When compared with control cultures, habituated CoNS cultures had higher (P < 0.05) MIC values against three‐fifths of the antibiotics examined; no changes in TTO MIC were observed. Conclusions: TTO habituation ‘stress‐hardens’ MRSA and MSSA, evidenced by transient decreased antibiotic susceptibility and stable decreased TTO susceptibility. Although TTO habituation did not decrease susceptibility of CoNS to TTO, such cultures showed transient decreased antibiotic susceptibility. Significance and Impact of the Study: Application of TTO at sub‐lethal concentrations may reduce the efficacy of topical antibiotics used with TTO in combination therapies.     

Solid-phase synthesis and antibacterial activity of hydroxycinnamic acid amides and analogues against methicillin-resistant Staphylococcus aureus and vancomycin-resistant S. aureus

A library of hydroxycinnamic acid amides (HCAAs) and analogues were synthesized using solid-phase synthesis technique. These compounds were screened for antibacterial against methicillin-resistant Staphylococcus aureus (MRSA) (11 strains) and vancomycin-resistant S. aureus (VRSA) (4 strains). Dihydrocaffeoyl analogues showed activity against VRSA which were better than the reference drugs, vancomycin and oxacillin. These compounds also exhibited antibacterial activity against MRSA, which were more potent than oxacillin.     

Studies on the novel anti-staphyloccal compound nematophin

A number of analogues of the recently described compound nematophin were prepared and studied for antibacterial activity. The 2-phenyl derivative was found to exhibit exceptional activity against methicillin resistant Staphylococcus aureus (MRSA) whereas the isosteric benzimidazole analogue was much less active.     

Synthesis and structure-activity relationships of 2-vinylchroman-4-ones as potent antibiotic agents

A series of novel 2-vinylchroman-4-ones, analogues of the natural products Aposphaerin A and B, were identified as potent antibiotics. Derivatives exhibit a significant activity against multiresistant strains of S. aureus, such as MRSA (methicillin resistant S. aureus). The 2-vinylchroman-4-ones were efficiently prepared by Lewis acid mediated conjugate addition of vinylmagnesium bromide to chromones.     

Antibacterial properties of a new isoflavonoid from Erythrina poeppigiana against methicillin-resistant Staphylococcus aureus.

A new isoflavonoid, together with four known isoflavonoids, was isolated from the roots of Erythrina poeppigiana. The chemical structure was determined by extensive spectroscopic studies, and then its antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA) was investigated. The new isoflavonoid was identified as 3,9-dihyroxy-10-gamma,gamma-dimethylallyl-6a,11a-dehydropterocarpan (compound 1). Compound 1 inhibited bacterial growth most potently of the five isolates, and had a minimum inhibitory concentration (MIC) of 125 microg/ml against thirteen MRSA strains. Inhibitory activity was based on bactericidal action and viable cell number reduced by approximately 1/10,000 after 4 h incubation with compound 1. Despite intense bactericidal action against MRSA, compound 1 never resulted in leakage of 260 nm-absorbing substances from bacterial cells. Compound 1 (12.5 microg/ml) completely inhibited incorporation of radio-labeled thymidine, uridine and leucine into MRSA cells. Although glucose incorporation was also markedly inhibited by the compound, the amount of glucose incorporated by bacterial cells increased gradually with incubation time. These findings suggest that compound 1 exhibits anti-MRSA activity by interfering with incorporation of metabolites and nutrients into bacterial cells or by affecting the nucleic acids of MRSA cells. Furthermore, this new compound could be a potent phytotherapeutic agent for treating MRSA infections.     

Anti-MRSA cephems. Part 1: C-3 substituted thiopyridinium derivatives

Sixteen novel cephalosporin derivatives with activity against methicillin-resistant Staphylococcus aureus (MRSA) are described. The compounds were synthesized using substituted thiopyridones, generated either by cyclization of functionalized precursors, or by direct alkylation of the enolate of 2-methyl substituted pyrones. The most active compound in vitro against a strain of MRSA (A27223) displayed an MIC of 0.5 microg/mL. The most efficacious compound in vivo had a PD50 of 2.1 mg/kg.     

Synthesis and antimicrobial activity of some new thiazolyl thiazolidine-2,4-dione derivatives

In this study, a series of thiazolyl thiazolidine-2,4-dione derivatives (Va-f and VIa-f) were synthesized and evaluated for their antibacterial and antifungal activities against Staphylococcus aureus (ATCC 25923), methicillin resistant S. aureus (MRSA ATCC 43300), methicillin resistant S. aureus (MRSA isolate), and Escherichia coli (ATCC 23556) and C. albicans (ATCC10145). All the compounds were found active against used microorganisms.     

The anti-staphylococcal activity of Angelica dahurica (Bai Zhi)

Bioassay-guided fractionation of a hexane extract prepared from the roots of the Chinese drug Angelica dahurica (Bai Zhi) led to the isolation of the polyacetylenic natural product falcarindiol (1). The absolute stereochemistry of this compound was confirmed by careful 1H NMR analysis of its (R)- and (S)-Mosher ester derivatives as the 3(R), 8(S) isomer. Activity was tracked using a Mycobacterium fortuitum screening assay and the purified product was evaluated against multidrug-resistant and methicillin-resistant strains of Staphylococcus aureus (MRSA). The minimum inhibitory concentrations (MIC) of this metabolite ranged from 8 to 32 microg/ml highlighting the potential of the acetylene natural product class as antibiotic-lead compounds. These MIC values compare favourably with some of the newest agents in development for the treatment of MRSA infection and indicate that further evaluation of the antibiotic activity of acetylenes is warranted.     

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。     

Methicillin‐resistant Staphylococcus aureus carriage among veterinary staff and dogs in private veterinary clinics in Hokkaido,Japan

To explore the prevalence and molecular characteristics of methicillin‐resistant Staphylococcus aureus (MRSA) in veterinary medical practices, MRSA carriage was tested among 96 veterinarians (Vets), 70 veterinary technicians (VTs) and 292 dogs with which they had contact at 71 private veterinary clinics (VCs) in Hokkaido, Japan. MRSA isolates were obtained from 22 Vets [22.9%] and 7 VTs [10%]. The prevalence of MRSA among Vets was as high as that found in an academic veterinary hospital in our previous study. In contrast, only two blood donor dogs and one dog with liver disease (1.0%, 3/292) yielded MRSA. All MRSA‐positive dogs were reared or treated in different VCs, in each of which at least one veterinary staff member carrying MRSA worked. Sequence types (ST) identified by multilocus sequence typing, spa types, and SCCmec types for canine MRSA isolates (ST5‐spa t002‐SCCmec II [from two dogs] or ST30‐spa t021‐SCCmec IV [from a dog]) were concordant with those from veterinary staff members in the same clinics as the MRSA‐positive dogs, with which they had potentially had contact. Most MRSA isolates from veterinary staff were the same genotype (SCCmec type II and spa type t002) as a major hospital‐acquired MRSA clone in Japan. The remaining MRSA was the same genotypes as domestic and foreign community‐associated MRSA. Measures against MRSA infection should be provided in private VCs.     

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   

Pyrrolidine bis-cyclic guanidines with antimicrobial activity against drug-resistant Gram-positive pathogens identified from a mixture-based combinatorial library

The rapid rise in antibiotic-resistant Gram-positive bacterial infections prompted us to explore the development of novel strategies for synthesis of large chemical libraries amenable to high-throughput screening for antimicrobial activities. Here we report the solid-phase synthesis of a 738,192 member pyrrolidine bis-cyclic guanidine chemical library with 26 different amino acids at three positions of diversity and 42 carboxylic acids at the fourth position. This synthetic combinatorial library was developed for positional scanning and screened for bacteriostatic and bactericidal activities against the important human pathogen methicillin-resistant Staphylococcus aureus (MRSA). The eight compound mixtures exhibiting bactericidal activity (10 microg/mL) against MRSA were used to direct the synthesis of 36 individual compounds that were then screened for activity against MRSA, vancomycin-resistant Enterococcus faecalis (VRE), and two Gram-negative bacterial species. At least 20 individual compounds were bactericidal for MRSA at 2.5 microg/mL, with a subset of these compounds showing bactericidal activities (10 microg/mL) against the other species tested. This approach demonstrates the capability to synthesize and screen a complex library to yield promising antimicrobials that address a critical need for novel infectious disease therapeutics.