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Janish Desai Dr. Yang Wang Dr. Ke Wang Dr. Satish R. Malwal Prof. Eric Oldfield 《ChemMedChem》2016,11(19):2205-2215
We synthesized potential inhibitors of farnesyl diphosphate synthase (FPPS), undecaprenyl diphosphate synthase (UPPS), or undecaprenyl diphosphate phosphatase (UPPP), and tested them in bacterial cell growth and enzyme inhibition assays. The most active compounds were found to be bisphosphonates with electron‐withdrawing aryl‐alkyl side chains which inhibited the growth of Gram‐negative bacteria (Acinetobacter baumannii, Klebsiella pneumoniae, Escherichia coli, and Pseudomonas aeruginosa) at ~1–4 μg mL?1 levels. They were found to be potent inhibitors of FPPS; cell growth was partially “rescued” by the addition of farnesol or overexpression of FPPS, and there was synergistic activity with known isoprenoid biosynthesis pathway inhibitors. Lipophilic hydroxyalkyl phosphonic acids inhibited UPPS and UPPP at micromolar levels; they were active (~2–6 μg mL?1) against Gram‐positive but not Gram‐negative organisms, and again exhibited synergistic activity with cell wall biosynthesis inhibitors, but only indifferent effects with other inhibitors. The results are of interest because they describe novel inhibitors of FPPS, UPPS, and UPPP with cell growth inhibitory activities as low as ~1–2 μg mL?1. 相似文献
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Gramicidin A Mutants with Antibiotic Activity against Both Gram‐Positive and Gram‐Negative Bacteria 下载免费PDF全文
Antimicrobial peptides (AMPs) have shown potential as alternatives to traditional antibiotics for fighting infections caused by antibiotic‐resistant bacteria. One promising example of this is gramicidin A (gA). In its wild‐type sequence, gA is active by permeating the plasma membrane of Gram‐positive bacteria. However, gA is toxic to human red blood cells at similar concentrations to those required for it to exert its antimicrobial effects. Installing cationic side chains into gA has been shown to lower its hemolytic activity while maintaining the antimicrobial potency. In this study, we present the synthesis and the antibiotic activity of a new series of gA mutants that display cationic side chains. Specifically, by synthesizing alkylated lysine derivatives through reductive amination, we were able to create a broad selection of structures with varied activities towards Staphylococcus aureus and methicillin‐resistant S. aureus (MRSA). Importantly, some of the new mutants were observed to have an unprecedented activity towards important Gram‐negative pathogens, including Escherichia coli, Klebsiella pneumoniae and Psuedomonas aeruginosa. 相似文献
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Christopher C Perry Monique Weatherly Tiffany Beale Alexandrine Randriamahefa 《Journal of the science of food and agriculture》2009,89(6):958-964
BACKGROUND: In this study the effects of ampicillin and aqueous garlic extract on Escherichia coli (ATCC 9637) and Staphylococcus aureus (ATCC 25923) were compared. Atomic force microscopy (AFM) was used to study the possible mechanisms of membrane disruption. RESULTS: Ampicillin disrupted the cell membrane of E. coli, inducing pores and cell leakage. Aqueous garlic extract also induced leakage from the cell membrane in E. coli, but no pores were observed. The trend in Young's modulus for E. coli was Enative ≈ Eage > Eamp. In contrast, S. aureus incubated with low ampicillin (≤50µg mL?1) and garlic (≤50 mg mL?1) concentrations showed no significant changes in surface morphology compared with the untreated bacterium. The trend in Young's modulus for S. aureus was Enative ≈ Eage ≈ Eamp. CONCLUSION: The trend Enative ≈ Eage for E. coli and S. aureus supports the hypothesis that the compounds in garlic show intracellular activity. This proof‐of‐concept study of the aqueous crude isolate of garlic points to the feasibility of further AFM investigations to compare the antimicrobial properties of various pure thiosulfinate isolates found in garlic. Copyright © 2009 Society of Chemical Industry 相似文献
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Claude J. RENAUD Xuling LIN Srinivas SUBRAMANIAN Dale A. FISHER 《Hemodialysis international. International Symposium on Home Hemodialysis》2011,15(1):63-68
Methicillin‐sensitive Staphylococcus aureus (MSSA) bacteremia is a leading cause of infection in hemodialysis (HD) patients. Cloxacillin, cefazolin, and vancomycin are the mainstay antimicrobials. Cloxacillin administration leads to frequent drug dosing, longer length of stay (LOS), and higher cost, while resistance and poorer outcomes are associated with vancomycin use. Dosing cefazolin during HD allows for prolonged blood therapeutic levels. We assessed the outcomes and safety of a strategy of treating MSSA bacteremia with 2–3 g cefazolin on HD only. All HD patients with MSSA bacteremia admitted in June–December 2009 at our center and receiving this regime were compared with historical controls who received cloxacillin. Demographic characteristics and outcome measures like mortality, LOS, cost, recrudescence, and adverse drug reactions were assessed. Of 27 consecutive episodes reviewed, 14 and 13 patients received cefazolin and cloxacillin, respectively. Baseline demographics were comparable between the 2 treatment groups. More than one‐third of the bacteremia was related to tunneled catheter infection. The 30‐day mortality of cloxacillin‐ and cefazolin‐treated patients was 15% and 7%, respectively (P=0.14). Two of the 11 survivors treated with cloxacillin (18%) had recrudescent bacteremia while none was observed in cefazolin‐treated survivors. Cefazolin was associated with shorter LOS (10 vs. 20 days, P<0.05) and lower cost (US$8262.00 vs. US$15,367.00, P<0.05). Cefazolin use resulted in 3 idiosyncratic adverse drug reactions. Cefazolin dosed on each HD in MSSA bacteremia leads to earlier discharge and less cost. Larger prospective studies are, however, warranted to fully assess its safety and efficacy. 相似文献
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Staphylococcus aureus, a Gram-positive organism, is responsible for numerous infections ranging in severity from skin and soft tissue infections to endocarditis and septic arthritis. Further, Staphylococcal food poisoning (SFP) caused by enterotoxigenic staphylococci is one of the main food-borne diseases. In this study, several single-seed origin clonal lines of herbs from Lamiaceae family were screened for antimicrobial applications against S. aureus. These clonal lines have consistent total phenolic content, phenolic profile and antioxidant activity as opposed to heterogenous phenolic profiles of typical herbal extracts. The clonal extracts of specific herb species were evaluated for anti- S. aureus activity. Water extracts of clonal lemon balm had the highest anti- S. aureus activity followed by clonal extracts of rosemary RoLA, sage, oregano, rosemary Ro-6, rosemary RoK-2 and chocolate mint. The anti- S. aureus activity of the water extracts correlated with gallic acid and caffeic acid content, which in pure form showed high anti- S. aureus activity. Based on the rationale that gallic acid and caffeic acid were likely proline analogs affecting proline oxidation, the countering effect of proline to overcome their anti- S. aureus activity was evaluated. Results indicated proline can overcome the inhibitory effects of gallic acid and caffeic acid. These results point to the likely role of phenolic oxidation via proline dehydrogenase, which could be an important target for inhibition by phenolic phytochemicals behaving as proline analog mimics. This mode of regulation by phenolics at the bacterial proline dehydrogenase in the plasma membrane may be an important antimicrobial defense in plants and has consequences for disruption of critical energy metabolism of invading bacterial pathogen. This rationale could be used to design new antimicrobial strategies against S. aureus and other relevant bacterial pathogens. 相似文献
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