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Browsing by Author "Alghamdi, Saad"

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    A Decade's Worth of Impact Dox Loaded Liposomes in Anticancer Activity
    (Daffodil International University, 22-11-01) Ghosh, Puja; Tiwari, Himja; Lakkakula, Jaya; Roy, Arpita; Emran, Talha Bin; Rashid, Summya; Alghamdi, Saad; Rajab, Bodour S.; Almehmadi, Mazen; Allahyani, Mamdouh; Aljuaid, Abdulelah; Alsaiari, Ahad Amer; Sharma, Rohit; Babalghith, Ahmad O.
    Clinically approved therapeutics associated with cancer are limited to mostly chemotherapy, surgery and radiotherapy in spite of the advancements in the biomedical field. Due to the cardiotoxicity and uncountable side effects brought by the prevailing treatment strategies, demands are growing for targeted drug delivery using nanomaterials. For this the most commonly used drug, doxorubicin (DOX) is encapsulated within several type of nanovesicles to observe their anticancer activity. Among them, DOX encapsulated liposomes gained popularity because of their clinical success and lower toxicity. To enhance their efficiency and site specific delivery, attempts are made to modify the liposomes by combining them with peptides, aptamers, antibodies etc to develop pH, thermal, UV-sensitive and electro-magnetic liposomal nanocarriers for controlled drug release. The novel strategies for the treatment of Breast, Lung, Liver, Pancreatic, Prostate, Ovarian, Cervical, Blood, Brain and Colon cancer using modified liposomes encapsulating DOX are illustrated in this review.
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    Anti-Pathogenic, Anti-Diabetic, Anti-Inflammatory, Antioxidant, and Wound Healing Efficacy of Datura metel L. Leaves
    (Daffodil International University, 22-07-09) Prasathkumar, Murugan; Anisha, Salim; Khusro, Ameer; Essa, Musthafa Mohamed; Chidambaram, Saravana Babu; Qoronfleh, M. Walid; Sadhasivam, Subramaniam; Sahibzada, Muhammad Umar Khayam; Alghamdi, Saad; Abdulaziz, Mazen Almehmadi j, Osama; Khandaker, Mayeen Uddin; Faruque, Mohammad Rashed Iqbal; Emran, Talha Bin
    Datura metel L. is an important medicinal plant of Solanaceae family which has extensive pharmacological properties. The present investigation was aimed to identify the presence of phytoconstituents and assess in vitro antibacterial, anti-biofilm, anti-diabetic, anti-inflammatory, antioxidant, cytotoxicity, and wound healing efficacy of D. metel leaves extract. Among different solvent extracts, methanolic extract showed higher amount of phenolic (124.61 ± 0.68 mg GAE/g), alkaloid (88.77 ± 1.01 mg AE/g), flavonoids (42.24 ± 0.18 mg QE/g), and tannins contents (38.72 ± 0.51 mg GAE/g). The extract exhibited not only significantly (P < 0.05) different antibacterial activities against pathogens tested but also showed maximum biofilm inhibition of 94, 88, and 92% against B. subtilis, MRSA, and E. coli, respectively. Anti-diabetic assay depicted 22.55 ± 0.62–79.41 ± 1.13% and 24.31 ± 1.47–72.59 ± 0.22% of α-amylase and α-glucosidase inhibition abilities of methanolic extract, respectively at varied concentrations. The methanolic extract showed potential anti-inflammatory effect (P < 0.05) by showing 28.11 ± 0.13, 34.94 ± 1.11, 55.73 ± 0.42, 73.28 ± 0.72, and 92.62 ± 1.33% of inhibition of protein denaturation at different concentrations with an IC50 value of 52.45 µg/mL. The extract revealed significant (P < 0.05) rate of ABTS scavenging, DPPH degradation, and reducing power assay in a concentration dependent manner. The cytotoxicity assay was demonstrated on L929 mouse fibroblast cell line and found > 90% of cell viability in the presence of methanolic extract, thereby indicating its non-toxicity effect. Wound healing assay indicated that methanolic extract at 50 µg/mL closed 100% of wound gap after 24 h with high rate of migration and proliferation. Furthermore, GC–MS chromatogram revealed the presence of several components in methanolic extract, including neophytadiene, hexadecanoic acid, and hentriacontane as principal phytoconstituents. In conclusion, methanolic extract of D. metel leaves could be used as potent therapeutic agent not only for treating metabolic diseases but also superficial chronic diabetic wounds.
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    Antibiotic Susceptibility Patterns of ES β L Producers Isolated from the Mobile Phones
    (Daffodil International University, 2022-05-27) NG, Manjula; Mayegowda, Shilpa Borehalli; Priyanka, L.; Priyanka, D.; Alghamdi, Saad; Choudary, Shalini; Sanchita, V.; Chishmitha, G.; Atwah, Banan; Alhindi, Zain; Islam, Fahadul
    Mobile phones have become an indispensable part of human lives for communication, education, and entertainment activities. This study aims to evaluate the diversity pattern of bacterial contaminants on mobiles and to check antibiotic resistance profiles in 105 samples. The study revealed a contamination of 51% in men and 49% in women, the highest in the 21- to 30-year age group, evidencing the extreme use of mobiles by teenagers. The study observed Gram-negative bacteria (63%) versus Gram-positive bacteria (37%). Overall, Gram-negative bacterial isolates showed the highest sensitivity to antibiotic nitrofurantoin (90%) and the lowest in ampicillin (35%). Gram positive has highest incidence of sensitivity towards tigecycline (100%) and lowest in cefoxitin (20%). ESβL producers were found to be 21.0% and highest being in Klebsiella oxytoca (35%) followed by Klebsiella pneumonia (31%). Staphylococcus pseudintermedius and Staphylococcus capitis have been identified on the mobile phones for the very first time. Interestingly, some soil microbes were also isolated and unfortunately found to have some antibiotic resistance like Raoultella ornithinolytica and Sphingomonas paucimobilis. The results revealed that mobiles were contaminated with multidrug-resistant (MDR) pathogens, and this study also showed that few of the saprophytic soil strains have antibiotic resistance, which can be an alarming situation that needs to be addressed.
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    Chemical Composition of Pumpkin (Cucurbita maxima) Seeds and Its Supplemental Effect on Indian Women With Metabolic Syndrome
    (Daffodil International University, 2022-08-12) Monica, Sarah Jane; John, Sheila; Madhanagopal, R.; Sivaraj, C.; Khusro, Ameer; Arumugam, P.; Gajda´cs, Ma´rio; Lydia, D. Esther; Sahibzada, Muhammad Umar Khayam; Alghamdi, Saad; Almehmadi, Mazen; Emran, Talha Bin
    This study aimed to investigate the effect of pumpkin (Cucurbita maxima) seed supplementation on the anthropometric measurements, biochemical parameters, and blood pressure (BP) of Indian women with metabolic syndrome (MetS). Initially, in vitro antioxidant activities of pumpkin seeds extract were assessed using standard methods. In vitro alpha-amylase, alpha-glucosidase, and dipeptidyl peptidase IV (DPP-IV) inhibition effects, along with glucose uptake assay using 3T3-L1 cell lines were performed to determine the antidiabetic effects of the seeds extract. Fatty acids and phytoconstituents were identified using gas chromatography-mass spectrometry (GC–MS). Indian women aged 30–50 years, having MetS were assigned either to intervention (n = 21) or control (n = 21) group on a random basis. Participants in the intervention group received 5 g of pumpkin seeds for 60 days. Participants in both intervention and control were advised to follow certain dietary guidelines throughout the study. Pumpkin seeds extract exhibited not only strong reducing power but also scavenged DPPH and ABTS●+ free radicals with low IC50 values. Pumpkin seeds inhibited alpha-amylase, alpha-glucosidase, and DPP-IV enzymes at varying concentrations with IC50 values of 138, 22, and 246 µg/mL, respectively. Furthermore, glucose uptake was enhanced by 213% at 300 ng/mL on the 3T3-L1 cell line. GC–MS analysis showed the presence of propyl piperidine, flavone, oleic acid, and methyl esters of fatty acids in the seed extract. On comparing the changes in mean reduction/ increment in the anthropometric measurements as well as biochemical parameters and BP between the groups, significant difference (P = 0.012) was observed only for fasting plasma glucose. Findings of the present study highlight the role of pumpkin seeds as a cost-effective adjunct in treating MetS.
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    Cyclodextrin Nanoparticles for Diagnosis and Potential Cancer Therapy
    (Daffodil International University, 22-09-08) Karthic, Anandakrishnan; Roy, Arpita; Lakkakula, Jaya; Alghamdi, Saad; Shakoori, Afnan; Babalghith, Ahmad O.; Emran, Talha Bin; Sharma, Rohit; Lima, Clara Mariana Gonçalves; Kim, Bonglee; Park, Moon Nyeo; Safi, Sher Zaman; Almeida, Ray Silva de; Coutinho, Henrique Douglas Melo
    Cancer is still one of the world’s deadliest health concerns. As per latest statistics, lung, breast, liver, prostate, and cervical cancers are reported topmost worldwide. Although chemotherapy is most widely used methodology to treat cancer, poor pharmacokinetic parameters of anticancer drugs render them less effective. Novel nano-drug delivery systems have the caliber to improve the solubility and biocompatibility of various such chemical compounds. In this regard, cyclodextrins (CD), a group of natural nano-oligosaccharide possessing unique physicochemical characteristics has been highly exploited for drug delivery and other pharmaceutical purposes. Their cup-like structure and amphiphilic nature allows better accumulation of drugs, improved solubility, and stability, whereas CDs supramolecular chemical compatibility renders it to be highly receptive to various kinds of functionalization. Therefore combining physical, chemical, and bio-engineering approaches at nanoscale to specifically target the tumor cells can help in maximizing the tumor damage without harming non-malignant cells. Numerous combinations of CD Nano composites were developed over the years, which employed photodynamic, photo thermal therapy, chemotherapy, and hyperthermia methods, particularly targeting cancer cells. In this review, we discuss the vivid roles of cyclodextrin nan composites developed for the treatment and theranostics of most important cancers to highlight its clinical significance and potential as a medical tool.
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    Cyclodextrin Nanoparticles in Targeted Cancer Theranostics
    (Europe Pub Med Central, 2023-08-03) Bose, Roshnee; Jayawant, Maharsh; Raut, Rajesh; Roy, Arpita; Alghamdi, Saad; Qusty, Naeem F.; Sharma, Rohit; Verma, Devvret; Khandaker, Mayeen Uddin; Almujally, Abdullah; Tamam, Nissren; Sulieman, Abdelmoneim
    The field of cancer nanotheranostics is rapidly evolving, with cyclodextrin (CD)-based nanoparticles emerging as a promising tool. CDs, serving as nanocarriers, have higher adaptability and demonstrate immense potential in delivering powerful anti-cancer drugs, leading to promising and specific therapeutic outcomes for combating various types of cancer. The unique characteristics of CDs, combined with innovative nanocomplex creation techniques such as encapsulation, enable the development of potential theranostic treatments. The review here focuses mainly on the different techniques administered for effective nanotheranostics applications of CD-associated complex compounds in the domain of cancer treatments. The experimentations on various loaded drugs and their complex conjugates with CDs prove effective in in vivo results. Various cancers can have potential nanotheranostics cures using CDs as nanoparticles along with a highly efficient process of nanocomplex development and a drug delivery system. In conclusion, nanotheranostics holds immense potential for targeted drug delivery and improved therapeutic outcomes, offering a promising avenue for revolutionizing cancer treatments through continuous research and innovative approaches.
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    Encapsulation of Lactic Acid Bacteria by Lyophilisation with Its Effects on Viability and Adhesion Properties
    (Daffodil International University, 2022-05-27) Patil, Abhinandan; Munot, Neha; Patwekar, Mohsina; Patwekar, Faheem; Ahmad, Irfan; Alraey, Yasser; Alghamdi, Saad; Kabrah, Ahmed; Dablool, Anas S.; Dablool, Anas S.; Islam, Fahadul
    Lactobacillus (LAB) genera are considered important functional food but are found to have a short shelf life. In this study, two LAB, Lactobacillus plantarum (Lp) and Lactobacillus rhamnosus (Lr), were isolated from sheep’s milk, and whole-genome sequencing was carried out by using 16s rRNA Illumina Nextseq, the Netherlands. The LAB were encapsulated by the lyophilisation technique using different lyoprotective pharmaceutical excipients. This process was carried out using a freeze dryer (U-TECH, Star Scientific Instruments, India). Shelf-life determination was carried out by a 12-month study using the viability survival factor (Vsf). The in vitro cell adhesion technique was carried out by using the red snapper fish along with autoaggregation and cell surface hydrophobicity as vital probiotic properties. It was observed that Lp has a significantly higher (P < 0.001) Vsf of 7.2, while Lr has a Vsf of 7 (P < 0.05) when both are encapsulated with 10% maltodextrin + 5% sucrose kept at 4°C for 12 months. The result demonstrated that Lp had significantly high (P < 0.05) cell adhesion, 96% ± 1.2 autoaggregation, and 6% cell surface hydrophobicity as compared to Lr. Moreover, this study demonstrated that lyophilised LAB with lyoprotective excipients enhances shelf life without any changes in probiotic properties when kept at 4°C exhibiting all its probiotic properties.
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    Investigating Polyphenol Nanoformulations for Therapeutic Targets against Diabetes Mellitus
    (Daffodil International University, 2022-06-21) Islam, Fahadul; Khadija, Jannatul Fardous; Islam, Md. Rezaul; Shohag, Sheikh; Mitra, Saikat; Alghamdi, Saad; Babalghith, Ahmad O.; Theyab, Abdulrahman; Rahman, Mohammad Tauhidur; Akter, Aklima; Mamun, Abdullah Al; Alhumaydhi, Fahad A.; Emran, Talha Bin
    Diabetes mellitus (DM) is a fatal metabolic disorder, and its prevalence has escalated in recent decades to a greater extent. Since the incidence and severity of the disease are constantly increasing, plenty of therapeutic approaches are being considered as a promising solution. Many dietary polyphenols have been reported to be effective against diabetes along with its accompanying vascular consequences by targeting multiple therapeutic targets. Additionally, the biocompatibility of these polyphenols raises questions about their use as pharmacological mediators. Nevertheless, the pharmacokinetic and biopharmaceutical properties of these polyphenols limit their clinical benefit as therapeutics. Pharmaceutical industries have attempted to improve compliance and therapeutic effects. However, nanotechnological approaches to overcome the pharmacokinetic and biopharmaceutical barriers associated with polyphenols as antidiabetic medications have been shown to be effective to improve clinical compliance and efficacy. Therefore, this review highlighted a comprehensive and up-to-date assessment of polyphenol nanoformulations in the treatment of diabetes and vascular consequences.
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    Polymer-Based Nanocarriers for Biomedical and Environmental Applications
    (De Gruyter, 2023-08-31) Idris, Dahir Sagir; Roy, Arpita; Pandit, Soumya; Alghamdi, Saad; Alsaiari, Ahad Amer; Abdulaziz, Osama; Alsharif, Abdulaziz; Khandaker, Mayeen Uddin; Faruque, Mohammad Rashed Iqbal
    Polymer-based nanocarriers are created from natural or synthetic polymers that are modified to form submicroscopic particles. The polymer matrix can be customized to provide specific properties, such as surface chemistry and flexibility. This allows the particles to be designed and used in different fields. They are promising nanomaterials that are used as therapeutic and diagnostic agents, and they have potential biomedical and environmental applications. These nanocarriers are polymers that can be engineered with other types of nanomaterials with different sizes, shapes, and compositions. They can deliver drugs or their cargo to a specific site with precisely controlled release. They have many advantages compared to traditional drug delivery carriers, including improved biocompatibility, reduced toxicity, and increased efficacy. In biomedical applications, polymer nanocarriers have been used as drug delivery carriers, cancer therapy, and gene therapy. In environmental applications, polymer nanocarriers are able to remove heavy metals and other contaminants from air and water bodies. In this review, a summary of recent fabrication, design, synthesis, characterisation, and various applications in the biomedical and environmental fields has been provided. The review also highlights the current challenges and prospects of evolving polymer nanocarriers.
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    Role of Antimicrobial Drug in the Development of Potential Therapeutics
    (Daffodil International University, 2022-05-05) Mayegowda, Shilpa Borehalli; NG, Manjula; Alghamdi, Saad; Atwah, Banan; Alhindi, Zain; Islam, Fahadul
    Population of the world run into several health-related emergencies among mankind and humans as it creates a challenge for the evolution of novel drug discoveries. One such can be the emergence of multidrug-resistant (MDR) strains in both hospital and community settings, which have been due to an inappropriate use and inadequate control of antibiotics that has led to the foremost human health concerns with a high impact on the global economy. So far, there has been application of two strategies for the development of anti-infective agents either by classical antibiotics that have been derived for their synthetic analogs with increased efficacy or screening natural compounds along with the synthetic compound libraries for the antimicrobial activities. However, need for newer treatment options for infectious diseases has led research to develop new generation of antimicrobial activity to further lessen the spread of antibiotic resistance. Currently, the principles aim to find novel mode of actions or products to target the specific sites and virulence factors in pathogens by a series of better understanding of physiology and molecular aspects of the microbial resistance, mechanism of infection process, and gene-pathogenicity relationship. The design various novel strategies tends to provide us a path for the development of various antimicrobial therapies that intends to have a broader and wider antimicrobial spectrum that helps to combat MDR strains worldwide. The development of antimicrobial peptides, metabolites derived from plants, microbes, phage-based antimicrobial agents, use of metal nanoparticles, and role of CRISPR have led to an exceptional strategies in designing and developing the next-generation antimicrobials. These novel strategies might help to combat the seriousness of the infection rates and control the health crisis system.
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    Study of Certain Congenital Malformations Due to Low-Level Radiation Exposures From High Background Radiation Areas
    (Daffodil International University, 2022-06-15) JoJo, P.J.; Khandaker, Mayeen Uddin; Byju, S. Ben; Sunil, A.; Emran, Talha Bin; Osman, Hamid; Almalki, Mohammed; Alhumaydhi, Fahad A.; Alghamdi, Saad; Babalghith, Ahmad O.
    The coastal regions of some states (Kerala, Tamil Nadu, Andhra Pradesh and Orissa) in India are known to have plenty of thorium-rich minerals, therefore possess high external gamma radiation fields, and are identified as Natural High Background Radiation Areas. There are concerns about congenital malformations due to the high background radiation prevailing in the region. Therefore, scientists find interest to study the possible biological effects of low-level exposures on the local populace who are living with generations under these extraordinary radiation fields. The present study is an attempt to find the correlation between the incidences of certain congenital malformations through a 1:3 matched case-control study. A total of 75 subjects (58 mental retardation cases and 17 Cleft lip/palate cases) along with 225 controls were selected for the investigations. Indoor and outdoor gamma dose rates were measured using a halogen-quenched GM tube-based survey meter, while the indoor inhalation dose rates were measured based on the radon and progeny measurements using the twin cup dosimeters equipped with LR-115 Type II solid-state nuclear track detectors. Conditional logistic regression analysis was used to find out the correlation between the radiation dose with congenital malformation. This study found an insignificant risk of cleft lip/palate (but not for mental retardation) from the exposures to natural high external gamma radiation fields in the study area. Therefore, the results of the investigation indicate no explicit risk of congenital malformations by the high background natural radiation prevailing in the region.
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    Study of Certain Congenital Malformations Due to Low-Level Radiation Exposures From High Background Radiation Areas
    (Daffodil International University, 2022-06-15) JoJo, P.J.; Khandaker, Mayeen Uddin; Byju, S. Ben; Sunil, A.; Emran, Talha Bin; Osman, Hamid; Almalki j, Mohammed; Alhumaydhi, Fahad A.; Alghamdi, Saad; Babalghith, Ahmad O.
    The coastal regions of some states (Kerala, Tamil Nadu, Andhra Pradesh and Orissa) in India are known to have plenty of thorium-rich minerals, therefore possess high external gamma radiation fields, and are identified as Natural High Background Radiation Areas. There are concerns about congenital malformations due to the high background radiation prevailing in the region. Therefore, scientists find interest to study the possible biological effects of low-level exposures on the local populace who are living with generations under these extraordinary radiation fields. The present study is an attempt to find the correlation between the incidences of certain congenital malformations through a 1:3 matched case-control study. A total of 75 subjects (58 mental retardation cases and 17 Cleft lip/palate cases) along with 225 controls were selected for the investigations. Indoor and outdoor gamma dose rates were measured using a halogen-quenched GM tube-based survey meter, while the indoor inhalation dose rates were measured based on the radon and progeny measurements using the twin cup dosimeters equipped with LR-115 Type II solid-state nuclear track detectors. Conditional logistic regression analysis was used to find out the correlation between the radiation dose with congenital malformation. This study found an insignificant risk of cleft lip/palate (but not for mental retardation) from the exposures to natural high external gamma radiation fields in the study area. Therefore, the results of the investigation indicate no explicit risk of congenital malformations by the high background natural radiation prevailing in the region.
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    Synthesis of Biodiesel From Carthamus tinctorius L. Oil Using TiO2 Nanoparticles as a Catalyst
    (Scopus, 22-09-13) Jan, Hammad Ahmad; Saqib, Najm Us; Khusro, Ameer; Sahibzada, Muhammad Umar Khayam; Rauf, Mamoona; Alghamdi, Saad; Almehmad, Mazen; Khandaker, Mayeen Uddin; Emran, Talha Bin; Mohafez, Hamidreza
    Objectives The present study aimed to synthesize Titanium dioxide (TiO2) nanoparticles and assess its catalytic role in the synthesis of biodiesel from Carthamus tinctorius L. (a non-edible plant source). Methods The precipitation approach was used to synthesize TiO2 nanoparticles, and the process was verified using X-ray diffraction (XRD) and scanning electron microscope (SEM). The synthesized biodiesel was analyzed qualitatively through NMR, GC-MS, and FT-IR spectroscopy. Result XRD result showed that the crystal structure of TiO2 nanoparticles was a biphasic mixture of rutile and anatase phases. SEM analysis revealed that the synthesized TiO2 nanoparticles had size from 42 nm to 58 nm and a surface area of 21–27 m2/g. The oil content in the feedstock was 43.9 % with free fatty acids contents of 0.37 mg KOH/g. The suitable condition for optimum yield (95 %) of biodiesel was 1:10 of oil to methanol using 25 g of catalyst at a temperature of 65 °C for 80–120 min of reaction time. Results obtained through 1H NMR for methoxy proton at 3.661 ppm, an alpha-methylene proton in triplet from 2.015 to 2.788 ppm, terminal methyl protons at 0.885 to 0.910 ppm, and beta-carbonyl methylene protons from 1.253 to 1.641 ppm confirmed the synthesis of biodiesel. Similarly, the peaks obtained through FT-IR spectroscopy for methoxycarbonyl at 1740.6 cm−1 and ether at 1012.6 cm−1 are the evidence for the validation of transesterification reaction. Furthermore, GC-MS analysis showed peaks for 17 different types of fatty acid methyl esters. Conclusion The chemical and physical properties of C. tinctorius showed that the oil of C. tinctorius could be a potential non-edible feedstock for the biodiesel industries.
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    Vancomycin as an Antibacterial Agent Capped with Silver Nanoparticles
    (Daffodil International University, 2022-08-21) Patwekar, Mohsina; Patwekar, Faheem; Alghamdi, Saad; Kamal, Mehnaz; Allahyani, Mamdouh; Almehmadi, Mazen; Kabrah, Ahmed; Dablool, Anas S.; Alsaiari, Ahad Amer; Jawaid, Talha; Medikeri, Anuradha; Samuel, Krupa; Islam, Fahadul
    For the treatment of various infections, a variety of antimicrobial drugs are formulated. Nevertheless, many bacterial infections now exhibit antibiotic resistance due to the widespread utilization antibiotics. Methicillin-resistant among the most dangerous multidrug-resistant bacteria is Staphylococcus aureus (MRSA). Vancomycin became a viable therapy option due to MRSA resistance to methicillin medicines. One of the well-informed antibacterial compounds with wideband antibacterial activity is silver nanoparticles (AgNPs). AgNPs are thus suitable candidates for usage in conjunction alongside vancomycin to increase its antibacterial effect. The goal of the present research work is to boost the antibacterial potency of the glycopeptide antibiotic vancomycin towards Gram-positive (Staphylococcus aureus) but also Gram-negative (Escherichia coli) bacteria. The chemical reduction approach is used to create a colloidal solution of silver nanoparticles utilizing silver nitrate as a precursor in the environment of the ionic surfactant trisodium citrate that serves as covering including reducing reagent. Vancomycin was used to functionalize the synthesized nanoparticles and create the nanodrug complex (Van@AgNPs). The synergistic antibacterial potential of silver nanoparticles coated with vancomycin on both test pathogens was investigated using the agar well diffusion technique. The antibacterial potency for both classes of bacteria has significantly increased, according to the well diffusion test. It has been noted that this improvement is synergistic instead of additive.

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