Phytocompounds from Saudi Medicinal Plant Ziziphus nummularia against...

[Full title: Phytocompounds from Saudi Medicinal Plant Ziziphus nummularia against Vancomycin-Resistant Staphylococcus aureus (VRSA) Causing Atopic Dermatitis (AD)]

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OPEN ACCESS International Journal of Pharmacology ISSN 1811-7775 DOI: 10.3923/ijp.2023.655.664 Research Article Phytocompounds from Saudi Medicinal Plant Ziziphus nummularia against Vancomycin-Resistant Staphylococcus aureus (VRSA) Causing Atopic Dermatitis (AD) Muhammad Musthafa Poyil and Mohammed H. Karrar Alsharif Department of Basic Medical Sciences, College of Medicine, Prince Sattam bin Abdulaziz University, Al-Kharj 11942, Saudi Arabia Abstract Background and Objective: In Saudi Arabia, atopic dermatitis (AD) which is predominantly caused by Staphylococcus aureus including Vancomycin-Resistant Staphylococcus aureus (VRSA) results in severe suffering of patients. The present investigation analyses the potential of the crude methanolic extract of a Saudi medicinal herb, Ziziphus nummularia on vancomycin-resistant S. aureus . Materials and Methods: The collected Ziziphus nummularia was extracted using methanol and was screened against three stains (O-2, O-4 and O-5) of the VRSA clinical isolates by agar diffusion method. The minimum inhibitory concentrations (MICs) were determined and the extracts were analyzed for the detection of various phytochemicals. Thin layer chromatography and GC-MS analysis were also performed Results: Ziziphus nummularia was found to have phytocompounds with anti-VRSA activities. The activities were increased proportionally with the extract concentration and the MICs were found to be 0.39 mg mL G 1 for S. aureus O-5 and 0.781 mg mL G 1 for O-2 and O-4 strains The TLC separated the various fractions and the GC-MS result showed the presence of twenty-five bioactive phytocompounds Conclusion: In light of these findings, it could be suggested that, if developed through further studies, the crude Ziziphus nummularia can be used as a promising herbal formation for the treatment of atopic dermatitis Key words: Atopic dermatitis (AD), Ziziphus nummularia, phytochemicals, Vancomycin-Resistant Staphylococcus aureus (VRSA), Saudi medicinal plants Citation: Poyil, M.M. and M.H.K. Alsharif, 2023. Phytocompounds from Saudi medicinal plant Ziziphus nummularia against Vancomycin-Resistant Staphylococcus aureus (VRSA) causing atopic dermatitis (AD). Int. J. Pharmacol., 19: 655-664 Corresponding Author: Muhammad Musthafa Poyil, Department of Basic Medical Sciences, College of Medicine, Prince Sattam bin Abdulaziz University, Al-Kharj 11942, Saudi Arabia Tel: +966565634412 Copyright: © 2023 Muhammad Musthafa Poyil and Mohammed Hamid Karrar. This is an open access article distributed under the terms of the creative commons attribution License, which permits unrestricted use, distribution and reproduction in any medium, provided the original author and source are credited. Competing Interest: The authors have declared that no competing interest exists Data Availability: All relevant data are within the paper and its supporting information files.

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Int. J. Pharmacol., 19 (5): 655-664, 2023 INTRODUCTION Chronic inflammatory skin infection-atopic dermatitis (AD) affects about a quarter of the pediatric and up to 10% of the adult population worldwide and shows a tendency of increasing prevalence both at regional and global levels 1-6 People with allergic rhinitis, bronchial asthma, food allergies, etc., are more vulnerable to this disease and the patients usually suffer from skin itching which is severe at night, recurrent skin infections, eczema lesions in flexural areas and skin dryness. Atopic dermatitis has an adverse impact on the life quality of patients and their families as it causes disturbances in day-to-day activities and significant morbidity, in many cases 7 . It also burdens the countries with multi-million dollars of health expenses annually. The scenario in Saudi Arabia is also not different as various research in different parts of the kingdom have shown that the prevalence of the disease in all age groups from infants and children to adults is almost equal or slightly higher than the world average. The occurrence rates of atopic dermatitis adult population in various provinces of the Kingdom of Saudi Arabia varies from 6 to 13% 8 Across the world, Staphylococcus aureus is the most predominantly encountered bacterium responsible for atopic dermatitis and in Saudi Arabian adults with AD, the prevalence of this bacterium varied from 48.5 to 100% 9-13 . In Saudi children with AD, a study of their skin lesions showed that 65% of the causative bacteria were S. aureus . After the appearance of the Methicillin-Resistant Staphylococcus aureus (MRSA) in the 1960 s, vancomycin (VA) was the first agent of therapeutic choice. But, the incidents of multidrug-resistant bacterial pathogens including Vancomycin-Resistant Staphylococcus aureus (VRSA) have complicated the management of atopic dermatitis 14-16 . Clinical isolates of S. aureus from the kingdom have also shown resistance to a wide range of conventional antibiotics including vancomycin. This led the scientific world to search for new natural bioactive compounds with novel action modes against the Vancomycin-Resistant Staphylococcus aureus (VRSA) and the medicinal plants were always a potential option among them Since prehistoric times, plants have been used in treating diseases caused by microorganisms and facts like the increased bacterial resistance to conventional antibiotics have led to greater scientific attention to medicinal plants. Ziziphus nummularia , commonly known in Arabic as sidr is a thorny branched bush and a native to Saudi Arabia growing in dry and arid areas 17 . Various parts of Ziziphus nummularia have been applied to treat a wide variety of diseases through generations and in recent years, it has scientifically been proven that this plant possesses bioactive compounds responsible for antimicrobial, anti-inflammatory, antioxidant, anti-hypotensive, anti-hypoglycaemic, antitumor, liver protective and immune system stimulating properties 18,19 So, the study aims to use the novel antibacterial property of a plant of Saudi origin viz Ziziphus nummularia to treat a chronic disease-atopic dermatitis-that adversely affects the personal, family and social life of the patients and causes a huge financial burden on them MATERIALS AND METHODS Study area: The present study was conducted in the Basic Medical Sciences Laboratories of the College of Medicine at the Prince Sattam bin Abdulaziz University, Al-Kharj, Kingdom of Saudi Arabia from 03 January, 2022 to 16 February, 2023 Isolation and identification of S. aureus : Following standard sampling procedures, 23 specimens were collected from the infected lesions of the patients of PSA University Hospital. All the samples were preserved and immediately transported to the laboratory for further analysis. For identification, the isolated specimens were streaked on the mannitol salt agar (MSA) for golden-color colony formation. After that, the selected colonies were subjected to the selection of vancomycin-resistant strains. The selected isolates were observed for their gram reactions. The selected isolates of S. aureus were stored at 4 E C until further use Collection and extraction of Ziziphus nummularia : Ziziphus nummularia plants were collected from Al-Qassim City suburb of Central Saudi Arabia and the adherent dirt was removed by washing with running tap water and then air dried. To prepare the crude extract, 50 g of the clean, air dried plant material was put into 125 mL of methanol in a Soxhlet apparatus (Macherey-Nagel, Germany) (for 6-12 hrs). Using a hot air oven (model no. LDO 080 N, Lab Tech Instruments, Mumbai, India), the extract was evaporated by keeping it at 50 E C. In a cool dry place, the resulting powder was stored for further studies. The obtained crude extract powder was reconstituted in their respective solvents to the desired concentrations for the study. Using standard protocols, the crude methanolic extracts were further analyzed for the detection of various phytochemicals 20 Antibacterial activity analysis of crude methanolic extract of Ziziphus nummularia : The analyses to find out the anti-VRSA activities of the crude methanolic extract of Ziziphus nummularia against the three isolated vancomycinresistant S. aureus (O-2, O-4 and O-7) were carried out by agar diffusion technique 21 . For this, sterile plates of MHA (Mueller 656

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Int. J. Pharmacol., 19 (5): 655-664, 2023 Hinton Agar) were prepared and swabbed with overnight cultures of three VRSA (O-2, O-4 and O-5) and various concentrations of methanolic crude extract (0.125, 0.25, 0.5 and 1 g) were loaded into the respective wells and incubated for 24 hrs at 37 E C. The measurement (in mm) of the bacterial growth inhibition zones around the crude extract well indicated the anti-VRSA activity of the crude methanolic extract against three of the VRSA isolates (O-2, O-4 and O-5) Minimum inhibitory concentration (MIC) determination: The modified resazurin method 22 was used to find out the MIC of the crude methanolic extract of Ziziphus nummularia against the three isolated vancomycin-resistant S. aureus . Briefly, the serial dilution of crude extract was performed in muellerhinton broth (MHB) followed by the addition of overnight cultures of three VRSA (O-2, O-4 and O-5) and the plate was incubated. Then, the resazurin dye was added and incubated for 3 hrs and the color reduction from blue to pink indicated bacterial growth Thin layer chromatography (TLC) and GC-MS analysis: The crude extract was further analyzed for various fractions by TLC using silica gel as described by Mulik et al 23 . For the analysis, different mobile phases were used for different fractions such as tannin, saponin, flavonoids and phenols. The mobile phases used for tannin were n-butane:glacial CH COOH:water (4:1:5), ethyl acetate:toluene:Glacial acetic acid (40:30:5) for flavonoid, formic acid:toluene:acetone: (1:4.5:4.5) for phenol and saponin the mobile phase was water:n-butanol:acetic acid (14:84:7). The chromatography chamber was kept in the respective mobile phases for 20 min for equilibration. The air-dried sample loaded on the silica gel-coated plate was dipped in the solvent system for 45 min and then the respective reagents were sprayed on the plate for fraction detection. The reagents such as 1% FeCl 3 solution for tannin, 1% potassium ferrocyanide solution for flavonoid, Folin Ciocalteu reagent and Na 2 CO 3 solution for phenol and ethanol:sulphuric acid solution (freshly prepared, 90:10) followed by heating at 110 E C for 10 min for saponin detections were used. The presence of a spot on the plate indicated the detection of respective fractions from the crude extract of Ziziphus nummularia GC-MS (Gas Chromatography-Mass Spectrometry) analysis: The methanolic crude extract was subjected to GC-MS investigation for its chemical composition as described Khurshid et al 24 and Sinuany-Stern et al 25 . Before the analysis, all the important programs were initiated such as the temperature was regulated at 110-280 E C at the rate of 10 E C min G 1 , the carrier gas used was helium, column (dimensions: 30 m×0.25 mm×0.25 µm) and an injector temperature of 250 E C was adjusted. For analysis, 1 µL of the methanolic extract was injected and the analysis was continued for 30 min. Later, the separated compounds were eluted using a column and it was detected as peaks. Each peak in the chromatogram represented the individual molecule of the extract based on the retention time and area and also and the chemical constituentʼs identification was done by searching the library of the National Institute of Standards and Technology (NIST) 26 Statistical analysis: The data and statistical analyses were represented as mean±standard deviation and the statistical significance was considered, with a p<0.05. All the experiments were performed in triplicates RESULTS Crude extract and detection of phytochemicals: The crude methanolic extraction of Ziziphus nummularia was performed using the Soxhlet apparatus as shown in Fig. 1. Further, different phytocompounds present in the methanolic crude extract were detected by the standard procedure as shown in Fig. 2 and Table 1. As seen, the crude extract was composed of Fig. 1: Crude methanolic extract of Ziziphus nummularia Table 1: List of different phytocompounds present in the methanolic crude extract of Ziziphus nummularia Phytochemicals Result Tannins + Flavonoids + Saponins + Steroids - Terpenoids + Glycosides + Phenol + Alkaloids - Quinone + Proteins + 657

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Int. J. Pharmacol., 19 (5): 655-664, 2023 Fig. 2: Detection of different phytocompounds present in the methanolic crude extract of Ziziphus nummularia Fig. 3: Seven isolates growth on MSA for golden-coloured colony appearance various phytochemicals such as tannin, flavonoids, saponin, phenol, quinone, proteins, glycosides and terpenoids but, noticeably, the steroids and alkaloids were not detected Isolation and identification of vancomycin-resistant S. aureus : The collected specimens were subjected to the isolation of S. aureus and the isolates were observed for the growth on MSA plates presented in Fig. 3. Out of seven isolates, three were identified as S. aureus (O-2, O-4 and O-5) based on the golden color colonies on MSA plates. The identified isolates were analyzed for their resistant pattern to vancomycin which is displayed in Fig. 4. Among the seven isolates, three isolates of S. aureus (O-2, O-4 and O-5) showed visible resistance to vancomycin. Further, the vancomycinresistant S. aureus (O-2, O-4 and O-5) observed for Gram reactions are displayed in Fig. 5 (a-c), which shows Grampositive cocci clusters of strains O-2, O-4 and O-5 in subparts a, b and c, respectively Antibacterial activity of crude methanolic extract of Ziziphus nummularia : The antibacterial activity of various concentrations of methanolic crude extracts of Ziziphus nummularia investigated against three isolates of VRSA was displayed in Fig. 6 and the size of the zone of inhibitions was shown in Table 2. As seen in the figure and table, the diameters of the zones of bacterial growth inhibition were increased while increasing the concentration of methanolic extract of Ziziphus nummularia indicating the antibacterial activity against three vancomycin-resistant S. aureus (O-2, O-4 and O-5) 658

Int. J. Pharmacol., 19 (5): 655-664, 2023 Fig. 4: Identification of vancomycin-resistant S. aureus Fig. 5(a-c): Microscopic images of isolated three VRSA after gram staining, (a) O-2, (b) O-4 and (c) O-5 Table 2: Zone of inhibition against three vancomycin-resistant S. aureus (O-2, O-4 and O-5) Zone of inhibition (mm) -------------------------------------------------------------------------------------------------------------------------------------------------------------------- Quantity of extract 0.125 g 0.25 g 0.5 g 1 g Test organisms O-2 - 7 9 13 O-4 8 9 10 14 O-5 12 14 17 23 MIC determination: The MIC of methanolic crude extract of Ziziphus nummularia against three vancomycin-resistant S. aureus (O-2, O-4 and O-5) was determined using resazurin and the result has been displayed in Fig. 7. The minimum concentration of methanolic crude extract needed to inhibit the vancomycin-resistant S. aureus O-2 and O-4 was found to be 0.781 mg mL G 1 and for O-5, 0.39 mg mL G 1 was needed for growth inhibition. Thin layer chromatography and GC-MS: The crude methanolic extract of Ziziphus nummularia phytochemicals separated was presented in Fig. 8(a-d). As seen in the figures, various phytochemicals such as tannin, flavonoids, phenol and saponin were detected during TLC separation after spraying the respective reagents. Further, the crude extract analyzed by GC-MS based on area and retention time compared with the NIST library were presented in Fig. 9 and Table 3 659 (a) (b) (c)

[Find the meaning and references behind the names: Amino, Ester, Iii, Tris, Beta, Dec, Alpha]

Int. J. Pharmacol., 19 (5): 655-664, 2023 Fig. 6: Antibacterial activity of methanolic crude extract of Ziziphus nummularia against three vancomycin-resistant S. aureus (O-2, O-4 and O-5) Fig. 7: Visualization of MIC determination using resazurin dye reduction method Pink indicates bacterial growth whereas blue denotes no bacterial growth Fig. 8(a-d): TLC analysis of various phytochemicals detection, (a) Tannin, (b) Flavonoids, (c) Phenol and (d) Saponin The investigation using the GC-MS technique showed that there were twenty-five phytocompounds namely Tris(3- acetyltetramsaeure)-gadolinium(iii), Propanamide, 3-amino-3- imino-2-(4-methoxyphenylazo)-, 2-[p-Chlorophenoxy]- 5- nitropyridine, 7-Chloro-4-[[2-(1-methyl-2-pyrrolidinyl) ethyl] amino] -2-trichloromethyl quinazoline, phthalic anhydride, alpha-cubebene, eugenol, caryophyllene, methyl ester 3,7-dimethyl-1,6-octadien-3-yl ester, malonic acid, bicyclo[4.4.0]dec-1-ene, naphthalene, [4 ar-(4 a.alpha.,7.alpha.,8 a.beta.)], 2-isopropyl-5-methyl-9- 660 (a) (c) (d) (b)

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Int. J. Pharmacol., 19 (5): 655-664, 2023 Fig. 9: GC-MS analysis of a crude methanolic extract of Ziziphus nummularia Table 3: Chemical composition of crude methanolic extract of Ziziphus nummularia Compound name Retention time (RT) Area (%) Tris(3-acetyltetramsaeure)-gadolinium(iii) 4.875 6.37 Propanamide, 3-amino-3-imino-2-(4-methoxyphenylazo)- 5.964 1.50 2-[p-Chlorophenoxy]-5-nitropyridine 6.509 0.75 7-Chloro-4-[[2-(1-methyl-2-pyrrolidinyl) ethyl] amino]-2-trichloromethylquinazoline 8.519 1.03 Phthalic anhydride 10.064 1.36 Eugenol 10.475 1.29 Alpha-cubebene 10.819 9.41 Caryophyllene 11.341 17.00 Methyl ester 3,7-dimethyl-1,6-octadien-3-yl ester, Malonic acid 11.719 1.16 2-isopropyl-5-methyl-9-methylene, Bicyclo[4.4.0]dec-1-ene 11.886 0.96 Naphthalene, [4 aR-(4 a. alpha.,7. alpha.,8 a. beta.)], Decahydro-4 a-methyl-1-methylene-7-(1-methylethenyl)- 12.086 6.17 (1 H) Imidazole-4-acetonitrile 12.141 1.12 Caryophyllene oxide 13.052 4.55 2-hydroxy-3-methyl-5,5-bis(1-methylethyl)-, 4-Oxazolidinone 13.230 2.81 2,5-Cyclohexadiene-1,4-dione, 3-hydroxy-2-methyl-5-(1-methylethyl)- 13.319 0.82 Bicyclo[3.1.1]heptane, 2,6,6-trimethyl 15.230 4.45 Z-13-Octadecen-1-yl acetate 15.596 0.80 n-Hexadecanoic acid 16.252 6.01 9,12-Octadecadienoic acid (Z,Z)-, methyl ester 17.618 0.82 cis-13-Octadecenoic acid 17.663 1.87 Octadecanoic acid 17.841 1.92 2,4-Difluoroaniline 19.496 2.02 Phenol, 2-methyl-4-(1,1,3,3-tetramethylbutyl)- 20.462 1.72 2-Octene, (E)- 21.784 19.04 7-Hydroxy-2-trifluoromethyl phenothiazine 23.484 5.04 methylene, decahydro-4 a-methyl-1-methylene-7-(1- methylethenyl)-, Caryophyllene oxide, Z-13- Octadecen -1-yl acetate, 2-Octene, (E)-, 7-Hydroxy-2- trifluoromethylphenothiazine and 2,4-Difluoroaniline. In addition, among the twenty-five compounds 2-Octene, (E)- and Eugenol are prominent antibacterial compounds present in methanolic crude extract of Ziziphus nummularia 661 56000 54000 52000 50000 48000 46000 44000 42000 40000 38000 36000 34000 32000 30000 28000 26000 24000 22000 20000 18000 16000 14000 12000 10000 8000 6000 4000 2000 0 5.00 6.00 7.00 8.00 9.00 10.00 11.00 12.00 13.00 14.00 15.00 16.00 17.00 18.00 19.00 20.00 21.00 22.00 23.00 Time Abundance TIC: GC-MS-3-5942.D\data.ms

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Int. J. Pharmacol., 19 (5): 655-664, 2023 DISCUSSION Atopic dermatitis (AD) is one of the most prevalent dermal infections affecting all age groups 14 and causing various skin conditions varying from slight to severe abnormalities such as relapsing skin infections and eczema lesions 27,28 . The prevalence of atopic dermatitis is increasing due to the development and spread of multi-drug-resistant S. aureus . Thus, in this investigation, the methanolic crude extract of Ziziphus nummularia was investigated against three VRSA (Vancomycin-Resistant Staphylococcus aureus ). The investigation could prove the antimicrobial potentials of the extract which was investigated against three isolated VRSA and the activities were found to be increasing proportionally with the increase in the plant extract concentration. The MICs of the methanolic extract against all three VRSA were calculated as 0.39 mg mL G 1 against S. aureus O-5 and 0.781 mg mL G 1 of the extract against the other two strains-viz., S aureus O-2 and S. aureus O-4. The presence of phytochemicals was detected which included tannin, saponin, flavonoids and phenols but surprisingly, the steroids and alkaloids were not detected in the crude extract which was separated using TLC. The GC-MS analysis revealed that 2- Octene, (E)- and Eugenol were the most prominent antibacterial compounds present in the extract. A similar study was reported by Odongo et al 29 in which they evaluated the antibacterial activity of Toddalia asiatica , Aloe secundiflora , Camellia sinensis and Senna didymobotrya extracts against various clinically important organisms including S. aureus . The study revealed the potential antibacterial effect that was achieved when combining the Aloe secundiflora and Clonorchis sinensis extracts against S. aureus . The lowest inhibitory concentration calculated against S. aureus was 156.25 µg/well Akinduti et al 30 investigated the antibacterial activities of the extracts from various plants including Vernonia amygdalina , Azadirachta indica , Acalypha wilkesiana and Moringa oleifera against the isolated multi-drug resistance S. aureus which involved in soft tissue and skin infections and the result revealed the potential antibacterial of Vernonia amygdalina and Azadirachta indica with a MIC at 100 mg mL G 1 and 75 mg mL G 1 due to saponin, alkaloids and terpenoids which were present in the extracts. These findings suggested that the tested plant extracts might be an alternative herbal formation with potent bioactive compounds against S. aureus involved in skin and other soft tissue infections. The antibacterial activity of Calpurnia aurea extract and their fractions were evaluated against various clinically important bacterial pathogens including S. aureus . The antibacterial activity was proved against S. aureus and was due to all of the fractions present in the extract. There were other studies suggesting the efficiency of plant extracts like that of Calpurnia aurea , in which the phytochemicals such as saponin, tannin, flavonoids and alkaloids reportedly supported the skin infection treatment 31 . In another investigation, the crude extract of Artemisia afra leaf was evaluated against different clinically significant pathogens including S. aureus and has shown potential activities with MIC value at 12.5 mg mL G 1 concentration and the minimum bactericidal potential at 6.25 mg mL G 1 , suggesting that the extract was a less toxic and an inexpensive antibacterial agent from Artemisia afra against S. aureus 32 . Edet et al 33 screened the crude extract of Annona muricata for its activity against multi-drug resistant (MDR) S. aureus and the result showed the presence of different phytochemicals such as glycosides, flavonoids, saponin, alkaloids, polyphenols, hydroxyanthraquinones, anthraquinone, tannin and phlobatannins. The GC-MS study showed the presence of carbonic acid 2-dimethylaminoethyl propyl ester, 1-methyl-4- phenyl-5-thioxo-1,2,4-triazolidin-3-one and trichloromethane, bicyclo[4.1.0]heptan-2-one 6-methyl. Overall, all the results could suggest that the phytocompounds present in the crude methanolic extracts of Ziziphus nummularia were behind the anti-VRSA activities against bacterial pathogens involved in skin and skin tissue infection. Even though the plant subjected to phytochemical and anti-VRSA studies here is a medicinal herb, the present investigation was done only at the lab level. To make the phytocompounds responsible for the anti-VRSA activities in Ziziphus nummularia available at an application level, further in vivo studies are needed with detailed biocompatibility and cytotoxicity analyses CONCLUSION Atopic dermatitis (AD) is one of the most prevalent skin infections and when it is caused by multidrug-resistant strains of pathogenic bacterial species like that of Vancomycin- Resistant Staphylococcus aureus (VRSA), the treatment and management become challenging. As phytocompounds have been providing a ray of hope in the development of new antibacterial agents, the present investigation focused on the methanolic crude extract of Ziziphus nummularia which was evaluated against isolated three vancomycin-resistant S. aureus and the minimum inhibitory concentration was calculated. The presence of various phytochemicals was detected and further, the compounds like tannin, saponin, flavonoids and phenols were separated using TLC. The GC-MS analysis revealed several bio compounds, among them, 2-octene, (E)- and eugenol were the prominent antibacterial agents present in the crude extract. Overall, 662

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Int. J. Pharmacol., 19 (5): 655-664, 2023 Ziziphus nummularia is being suggested as a potential source of antibacterial compounds against atopic dermatitis (AD), particularly against those caused by vancomycin-resistant S. aureus SIGNIFICANCE STATEMENT The scientific investigation reported here was performed to understand the effect of crude methanolic extract from a Saudi medicinal plant Ziziphus nummularia on Vancomycin- Resistant Staphylococcus aureus (VRSA), which is a major causative agent in atopic dermatitis (AD) that is one of the most prevalent skin infections in Saudi Arabia which results in unprecedented sufferings for the patients. The extract was chemically studied and screened against clinically isolated VRSA strains. The study found that the phytocompounds have promising activities against the selected strains of VRSA which made us to strongly recommend for further studies to be conducted to develop the plant extract for its clinical use, which could become a blessing for such patients ACKNOWLEDGMENT The authors are grateful to the Deanship of Scientific Research, Prince Sattam bin Abdulaziz University, Al-Kharj, Saudi Arabia, for funding this research work (Research grant number: 2022/03/22350) under a specialized research grant program REFERENCES 1 Schuler, C.F., A.C. Billi, E. Maverakis, L.C. Tsoi and J.E. Gudjonsson, 2023. Novel insights into atopic dermatitis J. Allergy Clin. Immunol., 151: 1145-1154 2 Al Kindi, A., H. Williams, K. Matsuda, A.M. Alkahtani and C. Saville et al ., 2021. Staphylococcus aureus second immunoglobulin-binding protein drives atopic dermatitis via IL-33. J. Allergy Clin. Immunol., 147: 1354-1368.e 3 3 di Domenico, E.G., I. Cavallo, V. Bordignon, G. Prignano and I. 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