{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T12:02:27Z","timestamp":1789041747650,"version":"build-2803163510"},"reference-count":48,"publisher":"MDPI AG","issue":"22","license":[{"start":{"date-parts":[[2021,11,12]],"date-time":"2021-11-12T00:00:00Z","timestamp":1636675200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Staphylococcus aureus (S. aureus) is a common pathogen that causes various serious diseases, including chronic infections. Discovering new antibacterial agents is an important aspect of the pharmaceutical field because of the lack of effective antibacterial drugs. In our research, we found that one anti-S. aureus substance is actinomycin D, originating from Streptomyces parvulus (S. parvulus); then, we further focused on the anti-S. aureus ability and the omics profile of S. aureus in response to actinomycin D. The results revealed that actinomycin D had a significant inhibitory activity on S. aureus with a minimum inhibitory concentration (MIC) of 2 \u03bcg\/mL and a minimum bactericidal concentration (MBC) of 64 \u03bcg\/mL. Bacterial reactive oxygen species (ROS) increased 3.5-fold upon treatment with actinomycin D, as was measured with the oxidation-sensitive fluorescent probe DCFH-DA, and H2O2 increased 3.5 times with treatment by actinomycin D. Proteomics and metabolomics, respectively, identified differentially expressed proteins in control and treatment groups, and the co-mapped correlation network of proteomics and metabolomics annotated five major pathways that were potentially related to disrupting the energy metabolism and oxidative stress of S. aureus. All findings contributed to providing new insight into the mechanisms of the anti-S. aureus effects of actinomycin D originating from S. parvulus.<\/jats:p>","DOI":"10.3390\/ijms222212231","type":"journal-article","created":{"date-parts":[[2021,11,12]],"date-time":"2021-11-12T08:10:22Z","timestamp":1636704622000},"page":"12231","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":27,"title":["Multi-Omics Analysis Reveals Anti-Staphylococcus aureus Activity of Actinomycin D Originating from Streptomyces parvulus"],"prefix":"10.3390","volume":"22","author":[{"given":"Yuqi","family":"Lin","sequence":"first","affiliation":[{"name":"Guangdong Provincial Key Laboratory of Food Quality and Safety, College of Food Science, South China Agricultural University, Guangzhou 510642, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li","family":"Huang","sequence":"additional","affiliation":[{"name":"Guangdong Provincial Key Laboratory of Food Quality and Safety, College of Food Science, South China Agricultural University, Guangzhou 510642, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoyong","family":"Zhang","sequence":"additional","affiliation":[{"name":"Joint Laboratory of Guangdong Province and Hong Kong Region on Marine Bioresource Conservation and Exploitation, College of Marine Sciences, South China Agricultural University, Guangzhou 510642, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiajia","family":"Yang","sequence":"additional","affiliation":[{"name":"Guangdong Provincial Key Laboratory of Food Quality and Safety, College of Food Science, South China Agricultural University, Guangzhou 510642, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaodan","family":"Chen","sequence":"additional","affiliation":[{"name":"Guangdong Provincial Key Laboratory of Food Quality and Safety, College of Food Science, South China Agricultural University, Guangzhou 510642, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fengming","family":"Li","sequence":"additional","affiliation":[{"name":"Guangdong Provincial Key Laboratory of Food Quality and Safety, College of Food Science, South China Agricultural University, Guangzhou 510642, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun","family":"Liu","sequence":"additional","affiliation":[{"name":"Laboratory of Pathogenic Biology, The Marine Biomedical Research Institute, Dongguan Key Laboratory of Medical Bioactive Molecular Developmental and Translational Research, Guangdong Medical University, Zhanjiang 524023, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Riming","family":"Huang","sequence":"additional","affiliation":[{"name":"Guangdong Provincial Key Laboratory of Food Quality and Safety, College of Food Science, South China Agricultural University, Guangzhou 510642, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,11,12]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1146\/annurev-med-042711-140023","article-title":"Staphylococcal Infections: Mechanisms of Biofilm Maturation and Detachment as Critical Determinants of Pathogenicity","volume":"64","author":"Otto","year":"2013","journal-title":"Annu. Rev. Med."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Dong, L.-M., Huang, L.-L., Dai, H., Xu, Q.-L., Ouyang, J.-K., Jia, X.-C., Gu, W.-X., and Tan, J.-W. (2018). Anti-MRSA Sesquiterpenes from the Semi-Mangrove Plant Myoporum bontioides A. Gray. Mar. Drugs, 16.","DOI":"10.3390\/md16110438"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1824","DOI":"10.1016\/j.cclet.2018.10.025","article-title":"Spermine increases bactericidal activity of silver-nanoparticles against clinical methicillin-resistant Staphylococcus aureus","volume":"29","author":"Liu","year":"2018","journal-title":"Chin. Chem. Lett."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1093\/femsre\/fuz030","article-title":"Development of a vaccine against Staphylococcus aureus invasive infections: Evidence based on human immunity, genetics and bacterial evasion mechanisms","volume":"44","author":"Miller","year":"2020","journal-title":"FEMS Microbiol. Rev."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"150","DOI":"10.1097\/QCO.0000000000000353","article-title":"The role of methicillin-resistant Staphylococcus aureus in skin and soft tissue infections","volume":"30","author":"Bassetti","year":"2017","journal-title":"Curr. Opin. Infect. Dis."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Sharafutdinov, I.S., Pavlova, A.S., Akhatova, F.S., Khabibrakhmanova, A.M., Rozhina, E.V., Romanova, Y.J., Fakhrullin, R., Lodochnikova, O.A., Kurbangalieva, A.R., and Bogachev, M.I. (2019). Unraveling the Molecular Mechanism of Selective Antimicrobial Activity of 2(5H)-Furanone Derivative against Staphylococcus aureus. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20030694"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"362","DOI":"10.1128\/CMR.05022-11","article-title":"Predictors of Mortality in Staphylococcus aureus Bacteremia","volume":"25","author":"Jensen","year":"2012","journal-title":"Clin. Microbiol. Rev."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Lee, J.H., Kim, E., Choi, H., and Lee, J. (2017). Collismycin C from the micronesian marine bacterium Streptomyces sp. MC025 inhibits Staphylococcus aureus biofilm formation. Mar. Drugs., 15.","DOI":"10.3390\/md15120387"},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Cho, E., Kwon, O.-S., Chung, B., Lee, J., Sun, J., Shin, J., and Oh, K.-B. (2020). Antibacterial Activity of Chromomycins from a Marine-Derived Streptomyces microflavus. Mar. Drugs, 18.","DOI":"10.3390\/md18100522"},{"key":"ref_10","first-page":"2","article-title":"Immune evasion by Staphylococcus aureus","volume":"7","year":"2019","journal-title":"Microbiol. Spectr."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1007\/s10482-008-9241-3","article-title":"Friends and foes: Streptomycetes as modulators of plant disease and symbiosis","volume":"94","author":"Schrey","year":"2008","journal-title":"Antonie van Leeuwenhoek"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"551","DOI":"10.1007\/s00253-020-11064-2","article-title":"Streptomycetes as platform for biotechnological production processes of drugs","volume":"105","author":"Ferraiuolo","year":"2021","journal-title":"Appl. Microbiol. Biotechnol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1265","DOI":"10.4014\/jmb.1503.03005","article-title":"Metabolomics-Based Chemotaxonomic Classification of Streptomyces spp. and Its Correlation with Antibacterial Activity","volume":"25","author":"Lee","year":"2015","journal-title":"J. Microbiol. Biotechnol."},{"key":"ref_14","first-page":"15","article-title":"Effect of low doses of actinomycin D on neuroblastoma cell lines","volume":"4","author":"Cortes","year":"2016","journal-title":"Mol. Cancer."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1201","DOI":"10.1111\/jam.14543","article-title":"Streptomyces -derived actinomycin D inhibits biofilm formation via downregulating ica locus and decreasing production of PIA in Staphylococcus epidermidis","volume":"128","author":"Mu","year":"2019","journal-title":"J. Appl. Microbiol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1080\/08927014.2015.1125888","article-title":"Streptomyces-derived actinomycin D inhibits biofilm formation by Staphylococcus aureus and its hemolytic activity","volume":"32","author":"Lee","year":"2016","journal-title":"Biofouling"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"4284","DOI":"10.1093\/nar\/gkt084","article-title":"The structural basis of actinomycin D\u2013binding induces nucleotide flipping out, a sharp bend and a left-handed twist in CGG triplet repeats","volume":"41","author":"Lo","year":"2013","journal-title":"Nucleic Acids Res."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1016\/0022-2836(72)90259-8","article-title":"Stereochemistry of actinomycin binding to DNA: II. Detailed molecular model of actinomycin-DNA complex and its implications","volume":"68","author":"Sobell","year":"1972","journal-title":"J. Mol. Biol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"445","DOI":"10.1016\/0022-2836(92)90931-9","article-title":"Crystal structure of the 2:1 complex between d(GAAGCTTC) and the anticancer drug actinomycin D","volume":"225","author":"Kamitori","year":"1992","journal-title":"J. Mol. Biol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1038\/emm.1999.9","article-title":"Redox signaling: Hydrogen peroxide as intracellular messenger","volume":"31","author":"Rhee","year":"1999","journal-title":"Exp. Mol. Med."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"813","DOI":"10.1038\/nrm2256","article-title":"ROS as signalling molecules: Mechanisms that generate specificity in ROS homeostasis","volume":"8","author":"Toledano","year":"2007","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"541","DOI":"10.1089\/ars.2017.7425","article-title":"Biological Production, Detection, and Fate of Hydrogen Peroxide","volume":"29","author":"Winterbourn","year":"2018","journal-title":"Antioxid. Redox Sign."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Gene Ontology Consortium (2019). The Gene Ontology Resource: 20 years and still GOing strong. Nucleic Acids Res., 47, D330\u2013D338.","DOI":"10.1093\/nar\/gky1055"},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"The Gene Ontology Consortium (2021). The Gene Ontology resource: Enriching a GOld mine. Nucleic Acids Res., 49, D325\u2013D334.","DOI":"10.1093\/nar\/gkaa1113"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"378","DOI":"10.1016\/j.tim.2004.06.004","article-title":"Staphylococcus aureus: Superbug, super genome?","volume":"12","author":"Lindsay","year":"2004","journal-title":"Trends Microbiol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"e00020-18","DOI":"10.1128\/CMR.00020-18","article-title":"Methicillin-Resistant Staphylococcus aureus: Molecular Characterization, Evolution, and Epidemiology","volume":"31","author":"Lakhundi","year":"2018","journal-title":"Clin. Microbiol. Rev."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"7333","DOI":"10.2147\/IJN.S169935","article-title":"A review on nanosystems as an effective approach against infections of Staphylococcus aureus","volume":"13","author":"Zhou","year":"2018","journal-title":"Int. J. Nanomed."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"564","DOI":"10.1007\/s12668-016-0281-2","article-title":"HtrA Protease from Bacillus subtilis Suppresses the Bacterial Fouling of the Rat Skin Injuries","volume":"6","author":"Sharafutdinov","year":"2016","journal-title":"BioNanoScience"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"2246","DOI":"10.3389\/fmicb.2017.02246","article-title":"Antimicrobial Effects of Sulfonyl Derivative of 2(5H)-Furanone against Planktonic and Biofilm Associated Methicillin-Resistant and -Susceptible Staphylococcus aureus","volume":"8","author":"Sharafutdinov","year":"2017","journal-title":"Front. Microbiol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/s41598-018-21141-2","article-title":"Suppression of Staphylococcus aureus biofilm formation and virulence by a benzimidazole derivative, UM-C162","volume":"8","author":"Kong","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"10119","DOI":"10.1074\/jbc.274.15.10119","article-title":"The Identification of Primary Sites of Superoxide and Hydrogen Peroxide Formation in the Aerobic Respiratory Chain and Sulfite Reductase Complex of Escherichia coli","volume":"274","author":"Messner","year":"1999","journal-title":"J. Biol. Chem."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Zhang, Y.-M., Chen, H., He, C.-L., and Wang, Q. (2013). Nitrogen Starvation Induced Oxidative Stress in an Oil-Producing Green Alga Chlorella sorokiniana C3. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0069225"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"3098","DOI":"10.1016\/j.biortech.2010.10.055","article-title":"Growth and lipid accumulation properties of a freshwater microalga Scenedesmus sp. under different cultivation temperature","volume":"102","author":"Li","year":"2011","journal-title":"Bioresource Technol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"9124","DOI":"10.1021\/acs.jafc.6b03284","article-title":"Mechanism of Arachidonic Acid Accumulation during Aging in Mortierella alpina: A Large-Scale Label-Free Comparative Proteomics Study","volume":"64","author":"Yu","year":"2016","journal-title":"J. Agric. Food Chem."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1091","DOI":"10.1111\/j.1365-2958.2006.05179.x","article-title":"Poly-gamma-glutamate in bacteria","volume":"60","author":"Candela","year":"2006","journal-title":"Mol. Microbiol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"957","DOI":"10.1134\/S0006297908090010","article-title":"Aconitate hydratase of mammals under oxidative stress","volume":"73","author":"Matasova","year":"2008","journal-title":"Biochemistry (Moscow)"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1016\/j.bbabio.2017.12.004","article-title":"Biochemical studies of membrane bound Plasmodium falciparum mitochondrial L-malate:quinone oxidoreductase, a potential drug target","volume":"1859","author":"Hartuti","year":"2018","journal-title":"Biochim. Biophys. Acta (BBA)-Bioenerg."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"21575","DOI":"10.1074\/jbc.M112.343020","article-title":"Functional Expression and Extension of Staphylococcal Staphyloxanthin Biosynthetic Pathway in Escherichia coli","volume":"287","author":"Kim","year":"2012","journal-title":"J. Biol. Chem."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1749","DOI":"10.4315\/0362-028X.JFP-17-041","article-title":"Further Evidence of How Unbuffered Starvation at 4 \u00b0C Influences Listeria monocytogenes EGD-e, HCC23, F2365, and Scott A","volume":"80","author":"Jarvis","year":"2017","journal-title":"J. Food Prot."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"635","DOI":"10.1089\/ars.2017.7350","article-title":"Proline Metabolism in Cell Regulation and Cancer Biology: Recent Advances and Hypotheses","volume":"30","author":"Phang","year":"2019","journal-title":"Antioxidants Redox Signal."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"171","DOI":"10.3389\/fphys.2019.00171","article-title":"Effects of Early Intervention with Maternal Fecal Bacteria and Antibiotics on Liver Metabolome and Transcription in Neonatal Pigs","volume":"10","author":"Wan","year":"2019","journal-title":"Front. Physiol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1016\/0014-5793(96)00244-X","article-title":"Induction of beta-methylcrotonyl-coenzyme A carboxylase in higher plant cells during carbohydrate starvation: Evidence for a role of MCCase in leucine catabolism","volume":"383","author":"Aubert","year":"1996","journal-title":"FEBS Lett."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"19841","DOI":"10.1038\/srep19841","article-title":"Proteomic response of methicillin-resistant S. aureus to a synergistic antibacterial drug combination: A novel erythromycin derivative and oxacillin","volume":"6","author":"Liu","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"3225","DOI":"10.1128\/AEM.00238-13","article-title":"Role of the Phenylalanine-Hydroxylating System in Aromatic Substance Degradation and Lipid Metabolism in the Oleaginous Fungus Mortierella alpina","volume":"79","author":"Wang","year":"2013","journal-title":"Appl. Environ. Microbiol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"D36","DOI":"10.1093\/nar\/gks1195","article-title":"GenBank","volume":"41","author":"Benson","year":"2013","journal-title":"Nucleic Acids Res."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"231","DOI":"10.4067\/S0718-58392011000200008","article-title":"Antifungal activity of medicinal plant extracts against phytopathogenic fungus Alternaria spp","volume":"71","author":"Dellavalle","year":"2011","journal-title":"Chil. J. Agric. Res."},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"Dwivedi, S., Wahab, R., Khan, F., Mishra, Y., Musarrat, J., and Al-Khedhairy, A. (2014). Reactive Oxygen Species Mediated Bacterial Biofilm Inhibition via Zinc Oxide Nanoparticles and Their Statistical Determination. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0111289"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"359","DOI":"10.1038\/nmeth.1322","article-title":"Universal sample preparation method for proteome analysis","volume":"6","author":"Zougman","year":"2009","journal-title":"Nat. Methods"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/22\/12231\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T07:29:08Z","timestamp":1760167748000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/22\/12231"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,11,12]]},"references-count":48,"journal-issue":{"issue":"22","published-online":{"date-parts":[[2021,11]]}},"alternative-id":["ijms222212231"],"URL":"https:\/\/doi.org\/10.3390\/ijms222212231","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,11,12]]}}}