Deciphering the Antibacterial Mode of Action of Alpha-Mangostin on Staphylococcus epidermidis RP62A Through an Integrated Transcriptomic and Proteomic Approach

Abstract

Background: Alpha-mangostin (α-MG) is a natural xanthone reported to exhibit rapid bactericidal activity against Gram-positive bacteria, and may therefore have potential clinical application in healthcare sectors. This study sought to identify the impact of α-MG on Staphylococcus epidermidis RP62A through integrated advanced omic technologies.Methods: S. epidermidis was challenged with sub-MIC (0.875 μg/ml) of α-MG at various time points and the differential expression pattern of genes/proteins were analyzed in the absence and presence of α-MG using RNA sequencing and LC-MS/MS experiments. Bioinformatic tools were used to categorize the biological processes, molecular functions and KEGG pathways of differentially expressed genes/proteins. qRT-PCR was employed to validate the results obtained from these analyses.Results: Transcriptomic and proteomic profiling of α-MG treated cells indicated that genes/proteins affected by α-MG treatment were associated with diverse cellular functions. The greatest reduction in expression was observed in transcription of genes conferring cytoplasmic membrane integrity (yidC2, secA and mscL), cell division (ftsY and divlB), teichoic acid biosynthesis (tagG and dltA), fatty-acid biosynthesis (accB, accC, fabD, fabH, fabI, and fabZ), biofilm formation (icaA) and DNA replication and repair machinery (polA, polC, dnaE, and uvrA). Those with increased expression were involved in oxidative (katA and sodA) and cellular stress response (clpB, clpC, groEL, and asp23). The qRT-PCR analysis substantiated the results obtained from transcriptomic and proteomic profiling studies.Conclusion: Combining transcriptomic and proteomic methods provided comprehensive information about the antibacterial mode of action of α-MG. The obtained results suggest that α-MG targets S. epidermidis through multifarious mechanisms, and especially prompts that loss of cytoplasmic membrane integrity leads to rapid onset of bactericidal activity.

<p>Nanoparticle Drug Delivery Systems for α-Mangostin</p>

“…Its pharmacological activities are diverse: antibacterial, anti-allergic, anti-fungal, anti-inflammatory activity, antioxidant and anticancer. [1][2][3][4][5] Previous studies demonstrated that α-mangostin can act against cancer cells via multiple pathways, [38][39][40][41] including inhibiting fatty acid synthase, signalling human epidermal growth factor receptor 2 (HER2)/phosphatidylinositide 3-kinase (PI3K)/Akt and mitogen-activated protein kinase (MAPK). 6,42 Notwithstanding its excellent bioactivity, αmangostin has limited solubility in water (2.03 x 10 −4 mg/ L at 25ºC).…”

“…α-Mangostin, a xanthone derivative compound isolated from Garcinia mangostana L. peel extract, has myriad pharmacological effects: antibacterial, antifungal, anti-inflammatory, antiallergic, antioxidant and anticancer activities. [1][2][3][4][5] The anticancer activity indicates that α-mangostin might serve as a potent anticancer agent in lung, stomach, colon, cervical, pancreatic, prostate, mammary gland, chondrosarcoma, renal, skin, tongue mucoepidermoid and breast cancers. [6][7][8][9][10][11][12][13][14][15][16][17][18] However, αmangostin has low solubility in water (2.03 x 10 −4 mg/L at 25ºC), and many efforts have been made to improve it: structure modification, co-solvation, solid dispersion, emulsion, complexation and nanoparticle drug delivery systems.…”

Transporters and Efflux Pumps Are the Main Mechanisms Involved in Staphylococcus epidermidis Adaptation and Tolerance to Didecyldimethylammonium Chloride

“…The down-regulated fused signal recognition particle receptor (ftsY [SE0910]) is part of the S. epidermidis Sec secretion system, and is involved in cell division, as a highly energy demanding process. The expression of ftsY was also reduced when S. epidermidis cells were exposed to α-mangostin, a natural xanthone with antimicrobial activity [28]. This indicates another energy saving process as an adaptation response.…”

Natural Xanthones and Skin Inflammatory Diseases: Multitargeting Mechanisms of Action and Potential Application

“…Similarly, S. epidermidis did not develop resistance towards 2 despite continuous exposure at 0.38-3.05 μM across 19 passages in both planktonic and biofilm cells (Sivaranjani et al, 2017). A later study conducted by Sivaranjani et al (2019) revealed molecular antibacterial mechanisms of 2 on S. epidermidis by downregulating the expression of genes responsible for bacterial cytoplasmic membrane integrity, cell division, teichoic acid and fatty acid biosynthesis, as well as DNA replication and repair systems. The target on multiple metabolic pathways by 2 minimized the risk of resistance development which greatly increased the potential of the xanthone as anti-bacterial agents for acne treatment.…”