8 research outputs found
Identification of New Drug Candidates Against \u3cem\u3eBorrelia burgdorferi\u3c/em\u3e Using High-Throughput Screening
Lyme disease is the most common zoonotic bacterial disease in North America. It is estimated that .300,000 cases per annum are reported in USA alone. A total of 10%–20% of patients who have been treated with antibiotic therapy report the recrudescence of symptoms, such as muscle and joint pain, psychosocial and cognitive difficulties, and generalized fatigue. This condition is referred to as posttreatment Lyme disease syndrome. While there is no evidence for the presence of viable infectious organisms in individuals with posttreatment Lyme disease syndrome, some researchers found surviving Borrelia burgdorferi population in rodents and primates even after antibiotic treatment. Although such observations need more ratification, there is unmet need for developing the therapeutic agents that focus on removing the persisting bacterial form of B. burgdorferi in rodent and nonhuman primates. For this purpose, high-throughput screening was done using BacTiter-Glo assay for four compound libraries to identify candidates that stop the growth of B. burgdorferi in vitro. The four chemical libraries containing 4,366 compounds (80% Food and Drug Administration [FDA] approved) that were screened are Library of Pharmacologically Active Compounds (LOPAC1280), the National Institutes of Health Clinical Collection, the Microsource Spectrum, and the Biomol FDA. We subsequently identified 150 unique compounds, which inhibited .90% of B. burgdorferi growth at a concentration of ,25 µM. These 150 unique compounds comprise many safe antibiotics, chemical compounds, and also small molecules from plant sources. Of the 150 unique compounds, 101 compounds are FDA approved. We selected the top 20 FDA-approved molecules based on safety and potency and studied their minimum inhibitory concentration and minimum bactericidal concentration. The promising safe FDA-approved candidates that show low minimum inhibitory concentration and minimum bactericidal concentration values can be chosen as lead molecules for further advanced studies
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In vitro and in vivo evaluation of cephalosporins for the treatment of Lyme disease.
BackgroundLyme disease accounts for >90% of all vector-borne disease cases in the United States and affect ~300,000 persons annually in North America. Though traditional tetracycline antibiotic therapy is generally prescribed for Lyme disease, still 10%-20% of patients treated with current antibiotic therapy still show lingering symptoms.MethodsIn order to identify new drugs, we have evaluated four cephalosporins as a therapeutic alternative to commonly used antibiotics for the treatment of Lyme disease by using microdilution techniques like minimum inhibitory concentration (MIC) and the minimum bactericidal concentration (MBC). We have determined the MIC and MBC of four drugs for three Borrelia burgdorferi s.s strains namely CA8, JLB31 and NP40. The binding studies were performed using in silico analysis.ResultsThe MIC order of the four drugs tested is cefoxitin (1.25 µM/mL) > cefamandole (2.5 µM/mL), > cefuroxime (5 µM/mL) > cefapirin (10 µM/mL). Among the drugs that are tested in this study using in vivo C3H/HeN mouse model, cefoxitin effectively kills B. burgdorferi. The in silico analysis revealed that all four cephalosporins studied binds effectively to B. burgdorferi proteins, SecA subunit penicillin-binding protein (PBP) and Outer surface protein E (OspE).ConclusionBased on the data obtained, cefoxitin has shown high efficacy killing B. burgdorferi at concentration of 1.25 µM/mL. In addition to it, cefoxitin cleared B. burgdorferi infection in C3H/HeN mice model at 20 mg/kg
Screening of NCI-DTP Library to Identify New Drug Candidates for \u3cem\u3eBorrelia burgdorferi\u3c/em\u3e
Lyme disease is the most rapidly growing tick borne zoonotic disease of the Northern Hemisphere and is among the 10 most commonly reported nationally notifiable diseases in the United States.1 Clinical presentations include erythema migrans, fever, chills, muscle and joint pain.2, 3 Though these symptoms tend to fade away even without therapeutic intervention, a significant number of untreated patients develop arthritis and persistent myalgia following exposure to Borrelia burgdorferi.4 Furthermore, 10–20% of patients treated for Lyme disease develop symptoms considered typical, or even exaggerated, including muscle, joint pain and generalized fatigue5, 6. This condition is referred as post-treatment lyme disease syndrome (PTLDS)
Vaccinomics driven proteome-wide screening of Haemophilus influenzae for the prediction of common putative vaccine candidates
Haemophilus influenzae colonizes the respiratory tract and is associated with life-threatening invasive infections. The recent rise in its global prevalence, even in the presence of multiple vaccines, indicate an urgent need for developing cross-strain effective vaccine strategies. Our work focused on identifying the universally conserved antigenic regions of H. influenzae that can be used for developing new vaccines. A variety of bioinformatics tools were applied for the comprehensive geno-proteomic analysis of H. influenzae type “a” strain, as reference serotype, through which subcellular localization, essentiality, virulence, and non-host homology were determined. B and T-Cell epitope mapping of 3D protein structures were performed. Thereafter, molecular docking with HLA DRB1*0101 and comparative genome analysis established the candidature of identified regions. Based on the established vaccinomics criteria, five target proteins were predicted as novel vaccine candidates. Among these, 9 epitopic regions were identified that could regulate the lymphocyte activity through strong protein-protein interactions. Comparative genomic analysis exhibited that the identified regions were highly conserved among the different strains of H. influenzae. Based on multiple immunogenic factors, the five prioritized proteins and their predicted epitopes were identified as the ideal common putative vaccine candidate against typeable strains.The accepted manuscript in pdf format is listed with the files at the bottom of this page. The presentation of the authors' names and (or) special characters in the title of the manuscript may differ slightly between what is listed on this page and what is listed in the pdf file of the accepted manuscript; that in the pdf file of the accepted manuscript is what was submitted by the author
Anti-MRSA potential of biogenic silver nanoparticles synthesized from hydroponically grown Foeniculum vulgare
Background: Antimicrobial-resistant superbugs are rapidly spreading globally. Methicillin-resistant Staphylococcus aureus (MRSA) is one of these superbugs for which effective antibiotics are urgently required. The development of resistance against synthetic compounds has led to the study and utilization of plant based antimicrobial options due to a greater sensitivity against the phytochemcials obtained from them. Fennel (Foeniculum vulgare), a therapeutic, aromatic and nutritionally important herb that grows worldwide has a number of phytochemicals of medicinal importance. These phytochemicals also have the potential to reduce Ag+ to Ag0, thereby, making them available for the green synthesis of silver nanoparticles. Usually, fennel grows under cool environment in well-drained soil. However, it is possible to grow it hydroponically in soilless conditions using water-based mineral nutrient solutions. The technique helps in attaining higher yields of plant biomass and, hence, the phytochemicals. Purpose: This study aimed to prepare a silver nanoparticles based formulation against MRSA-induced skin and soft tissue infections, by using fennel extract (FEHydro) obtained from hydroponically grown plants for better biomass and higher phytochemical content. Methods: Plants grown in hydroponic system were compared with soil grown for growth rate and phytochemical content. Spectrophotometric comparison of total flavonoids, phenols, alkaloids, tannins, carbohydrates, proteins and lipids was carried out between hydroponic fennel extract (FEHydro) and soil grown fennel extract (FESoil). After establishing the efficacy of the hydroponically grown plants, their extract FEHydro was used for AgNPs green synthesis. Fennel extract fabricated AgNPs (FEHydroNP) were tested in vitro against MRSA through disc diffusion, turbidometric and time kill assays. The fennel extract (FEHydro) and AgNPs (FEHydroNP) were, then, formulated in a polyvinyl pyrrolidone and ethylene cellulose (PVP-EC) hydrogel and characterized through in vivo burn model in BALB/c mice. Results: The hydroponic system was found to give efficient plant biomass turnover with phytochemical content comparable to soil cultivated fennel. Hydroponic fennel gained 0.81 inches more height per week and 1.23 more secondary branches per week than soil cultivated fennel. Spherical AgNPs were successfully obtained from the fennel extract of hydroponically grown plants. Moreover, enhanced in vitro anti-MRSA potential of FE NPs was observed with MIC 625 µg/ml and MBC 12,500 µg/ml. In vivo infection elimination in 7 days and skin reepithelization were observed in gross examination and through Hematoxylin & Eosin (H&E) stained slides of treated mouse skin biopsy samples. Conclusion: This study suggests that the green-synthesized silver nanoparticles of Fennel showed a strong antibacterial effect against the clinical isolates of MRSA, both in vitro and in vivo, thereby, suggesting their potential use in plant-based complementary and alternative medicine
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In vitro and in vivo evaluation of cephalosporins for the treatment of Lyme disease.
BackgroundLyme disease accounts for >90% of all vector-borne disease cases in the United States and affect ~300,000 persons annually in North America. Though traditional tetracycline antibiotic therapy is generally prescribed for Lyme disease, still 10%-20% of patients treated with current antibiotic therapy still show lingering symptoms.MethodsIn order to identify new drugs, we have evaluated four cephalosporins as a therapeutic alternative to commonly used antibiotics for the treatment of Lyme disease by using microdilution techniques like minimum inhibitory concentration (MIC) and the minimum bactericidal concentration (MBC). We have determined the MIC and MBC of four drugs for three Borrelia burgdorferi s.s strains namely CA8, JLB31 and NP40. The binding studies were performed using in silico analysis.ResultsThe MIC order of the four drugs tested is cefoxitin (1.25 µM/mL) > cefamandole (2.5 µM/mL), > cefuroxime (5 µM/mL) > cefapirin (10 µM/mL). Among the drugs that are tested in this study using in vivo C3H/HeN mouse model, cefoxitin effectively kills B. burgdorferi. The in silico analysis revealed that all four cephalosporins studied binds effectively to B. burgdorferi proteins, SecA subunit penicillin-binding protein (PBP) and Outer surface protein E (OspE).ConclusionBased on the data obtained, cefoxitin has shown high efficacy killing B. burgdorferi at concentration of 1.25 µM/mL. In addition to it, cefoxitin cleared B. burgdorferi infection in C3H/HeN mice model at 20 mg/kg