{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,26]],"date-time":"2026-06-26T03:38:00Z","timestamp":1782445080014,"version":"3.54.5"},"reference-count":41,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2020,9,17]],"date-time":"2020-09-17T00:00:00Z","timestamp":1600300800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Antibiotics"],"abstract":"<jats:p>The emergence of drug-resistant Staphylococcus aureus is responsible for high morbidity and mortality worldwide. New therapeutic options are needed to fight the increasing antimicrobial resistance among S. aureus in the clinical setting. We, therefore, characterized the in silico absorption, distribution, metabolism, elimination, and toxicity (ADMET) and in vitro antimicrobial activity of 5-nitro-2-thiophenecarbaldehyde N-((E)-(5-nitrothienyl)methylidene)hydrazone (KTU-286) against drug-resistant S. aureus strains with genetically defined resistance mechanisms. The antimicrobial activity of KTU-286 was determined by CLSI recommendations. The ADMET properties were estimated by using in silico modeling. The activity on biofilm integrity was examined by crystal violet assay. KTU-286 demonstrated low estimated toxicity and low skin permeability. The highest antimicrobial activity was observed among pan-susceptible (Pan-S) S. aureus (minimal inhibitory concentration (MIC) 0.5\u20132.0 \u00b5g\/mL, IC50 = 0.460 \u00b5g\/mL), followed by vancomycin resistant S. aureus (VRSA) (MIC 4.0 \u00b5g\/mL, IC50 = 1.697 \u00b5g\/mL) and methicillin-resistant S. aureus (MRSA) (MIC 1.0\u201316.0 \u00b5g\/mL, IC50 = 2.282 \u00b5g\/mL). KTU-286 resulted in significant (p &lt; 0.05) loss of S. aureus biofilm integrity in vitro. Further studies are needed for a better understanding of safety, synergistic relationship, and therapeutic potency of KTU-286.<\/jats:p>","DOI":"10.3390\/antibiotics9090612","type":"journal-article","created":{"date-parts":[[2020,9,17]],"date-time":"2020-09-17T08:29:43Z","timestamp":1600331383000},"page":"612","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":31,"title":["Synthesis, ADMET Properties, and In Vitro Antimicrobial and Antibiofilm Activity of 5-Nitro-2-thiophenecarbaldehyde N-((E)-(5-Nitrothienyl)methylidene)hydrazone (KTU-286) against Staphylococcus aureus with Defined Resistance Mechanisms"],"prefix":"10.3390","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0237-9088","authenticated-orcid":false,"given":"Povilas","family":"Kavaliauskas","sequence":"first","affiliation":[{"name":"Division of Infectious Diseases, Department of Medicine, Weill Cornell Medicine of Cornell University, New York, NY 10065, USA"},{"name":"Institute of Infectious Diseases and Pathogenic Microbiology, 59115 Prienai, Lithuania"},{"name":"Biological Research Center, Lithuanian University of Health Sciences, 47181 Kaunas, Lithuania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Birute","family":"Grybaite","sequence":"additional","affiliation":[{"name":"Department of Organic Chemistry, Kaunas University of Technology, 50254 Kaunas, Lithuania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vytautas","family":"Mickevicius","sequence":"additional","affiliation":[{"name":"Department of Organic Chemistry, Kaunas University of Technology, 50254 Kaunas, Lithuania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3269-8058","authenticated-orcid":false,"given":"Ruta","family":"Petraitiene","sequence":"additional","affiliation":[{"name":"Division of Infectious Diseases, Department of Medicine, Weill Cornell Medicine of Cornell University, New York, NY 10065, USA"},{"name":"Institute of Infectious Diseases and Pathogenic Microbiology, 59115 Prienai, Lithuania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ramune","family":"Grigaleviciute","sequence":"additional","affiliation":[{"name":"Biological Research Center, Lithuanian University of Health Sciences, 47181 Kaunas, Lithuania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rita","family":"Planciuniene","sequence":"additional","affiliation":[{"name":"Institute of Microbiology and Virology, Lithuanian University of Health Sciences, 47181 Kaunas, Lithuania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philip","family":"Gialanella","sequence":"additional","affiliation":[{"name":"Department of Pathology, Montefiore Medical Center and Albert Einstein College of Medicine, New York, NY 10467, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alius","family":"Pockevicius","sequence":"additional","affiliation":[{"name":"Department of Veterinary Pathobiology, Lithuanian University of Health Sciences, 47181 Kaunas, Lithuania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6811-4467","authenticated-orcid":false,"given":"Vidmantas","family":"Petraitis","sequence":"additional","affiliation":[{"name":"Division of Infectious Diseases, Department of Medicine, Weill Cornell Medicine of Cornell University, New York, NY 10065, USA"},{"name":"Institute of Infectious Diseases and Pathogenic Microbiology, 59115 Prienai, Lithuania"},{"name":"Biological Research Center, Lithuanian University of Health Sciences, 47181 Kaunas, Lithuania"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,9,17]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"446","DOI":"10.3329\/jhpn.v29i5.8898","article-title":"Multidrug-resistant intestinal Staphylococcus aureus among self-medicated healthy adults in Amassoma, South-South, Nigeria","volume":"29","author":"Onanuga","year":"2011","journal-title":"J. Health Popul. Nutr."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"71","DOI":"10.4103\/0974-2727.119843","article-title":"Recurrent Challenges for Clinicians: Emergence of methicillin-resistant Staphylococcus aureus, vancomycin resistance, and current treatment options","volume":"5","author":"Tarai","year":"2013","journal-title":"J. Lab. Physicians"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1016\/j.jcm.2011.12.001","article-title":"Methicillin-resistant Staphylococcus aureus: An overview for manual therapists","volume":"11","author":"Green","year":"2012","journal-title":"J. Chiropr. Med."},{"key":"ref_4","unstructured":"Siddiqui, A.H., and Koirala, J. (2020). Methicillin Eesistant Staphylococcus aureus (MRSA), StatPearls."},{"key":"ref_5","first-page":"269","article-title":"Vancomycin resistance in Staphylococcus aureus","volume":"90","author":"McGuinness","year":"2017","journal-title":"Yale. J. Biol. Med."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1016\/j.jare.2019.10.005","article-title":"Vancomycin resistant Staphylococcus aureus infections: A review of case updating and clinical features","volume":"21","author":"Cong","year":"2020","journal-title":"J. Adv. Res."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1038\/nrmicro3161","article-title":"Adhesion, invasion and evasion: The many functions of the surface proteins of Staphylococcus aureus","volume":"12","author":"Foster","year":"2014","journal-title":"Nat. Rev. Microbiol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"e00135-17","DOI":"10.1128\/mSphere.00135-17","article-title":"Heparin mimics extracellular DNA in binding to cell surface-localized proteins and promoting Staphylococcus aureus biofilm formation","volume":"2","author":"Mishra","year":"2017","journal-title":"mSphere"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"11997","DOI":"10.1038\/srep11997","article-title":"Transcriptome analysis of the biofilm formed by methicillin-susceptible Staphylococcus aureus","volume":"5","author":"Tan","year":"2015","journal-title":"Sci. Rep."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"e01365-16","DOI":"10.1128\/mBio.01365-16","article-title":"Commensal protection of Staphylococcus aureus against antimicrobials by Candida albicans biofilm matrix","volume":"7","author":"Kong","year":"2016","journal-title":"mBio"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"e01573-17","DOI":"10.1128\/AAC.01573-17","article-title":"Modulation of Staphylococcus aureus response to antimicrobials by the Candida albicans quorum sensing molecule farnesol","volume":"61","author":"Kong","year":"2017","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"625","DOI":"10.1080\/21505594.2019.1635418","article-title":"Candida albicans quorum-sensing molecule farnesol modulates staphyloxanthin production and activates the thiol-based oxidative-stress response in Staphylococcus aureus","volume":"10","author":"Vila","year":"2019","journal-title":"Virulence"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1186\/s13065-018-0511-5","article-title":"Therapeutic importance of synthetic thiophene","volume":"12","author":"Shah","year":"2018","journal-title":"Chem. Cent. J."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"68","DOI":"10.1186\/s13065-018-0437-y","article-title":"Heterocyclization of polarized system: Synthesis, antioxidant and anti-inflammatory 4-(pyridin-3-yl)-6-(thiophen-2-yl) pyrimidine-2-thiol derivatives","volume":"12","author":"Shehab","year":"2018","journal-title":"Chem. Cent. J."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1316","DOI":"10.1002\/cmdc.200800136","article-title":"Rational design and synthesis of 2,2-bisheterocycle tandem derivatives as non-nucleoside hepatitis B virus inhibitors","volume":"3","author":"Chen","year":"2008","journal-title":"ChemMedChem"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"172","DOI":"10.1016\/j.cbi.2017.05.005","article-title":"Synthesis, cytotoxicity and antifungal activity of 5-nitro-thiophene-thiosemicarbazones derivatives","volume":"272","author":"Buonafina","year":"2017","journal-title":"Chem. Biol. Interact."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1016\/j.ejmech.2014.08.047","article-title":"Synthesis of novel 1,2,4-triazoles, triazolothiadiazines and triazolothiadiazoles as potential anticancer agents","volume":"86","author":"Kamel","year":"2014","journal-title":"Eur. J. Med. Chem."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Mabkhot, Y.N., Alatibi, F., El-Sayed, N.N., Kheder, N.A., and Al-Showiman, S.S. (2016). Synthesis and structure-activity relationship of some new thiophene-based heterocycles as potential antimicrobial agents. Molecules, 21.","DOI":"10.3390\/molecules21081036"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1186\/s13065-017-0307-z","article-title":"Antimicrobial activity of thiophene derivatives derived from ethyl (E)-5-(3-(dimethylamino)acryloyl)-4-methyl-2-(phenylamino)thiophene-3-carboxylate","volume":"11","author":"Mabkhot","year":"2017","journal-title":"Chem. Cent. J."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1344","DOI":"10.1021\/tx500134g","article-title":"Bioactivation potential of thiophene-containing drugs","volume":"27","author":"Gramec","year":"2014","journal-title":"Chem. Res. Toxicol."},{"key":"ref_21","unstructured":"David, W., Henry, T., William, T., and Colwell, W.T. (1973). Nitrothiophenes. (3,733,319), U.S. Patent."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1196","DOI":"10.1016\/j.ejmech.2006.04.009","article-title":"A duplicated nitrotienyl derivative with antimycobacterial activity: Synthesis, X-ray crystallography, biological and mutagenic activity tests","volume":"41","author":"Rando","year":"2006","journal-title":"Eur. J. Med. Chem."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"84","DOI":"10.1111\/cbdd.13386","article-title":"Design and synthesis of 5-(5-nitrothiophen-2-yl)-3-phenyl-4,5-dihydro-1H-pyrazole derivatives with improved solubility and potential antituberculosis activity","volume":"93","author":"Khambete","year":"2019","journal-title":"Chem. Biol. Drug Des."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"4229","DOI":"10.1016\/j.bmc.2007.03.068","article-title":"A new class of nifuroxazide analogues: Synthesis of 5-nitrothiophene derivatives with antimicrobial activity against multidrug-resistant Staphylococcus aureus","volume":"15","author":"Masunari","year":"2007","journal-title":"Bioorg. Med. Chem."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"775","DOI":"10.1002\/jat.2938","article-title":"Assessment of the genotoxic and carcinogenic potentials of 3-aminothiophene derivatives using in vitro and in silico methodologies","volume":"34","author":"Lepailleur","year":"2014","journal-title":"J. Appl. Toxicol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"62","DOI":"10.3389\/fcimb.2012.00062","article-title":"Deciphering mechanisms of staphylococcal biofilm evasion of host immunity","volume":"2","author":"Hanke","year":"2012","journal-title":"Front. Cell Infect. Microbiol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"555","DOI":"10.1111\/j.1476-5381.2010.00930.x","article-title":"The 5-lipoxygenase inhibitor, zileuton, suppresses prostaglandin biosynthesis by inhibition of arachidonic acid release in macrophages","volume":"161","author":"Rossi","year":"2010","journal-title":"Br. J. Pharmacol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"445","DOI":"10.4161\/viru.2.5.17724","article-title":"Staphylococcus aureus biofilms: Properties, regulation, and roles in human disease","volume":"2","author":"Archer","year":"2011","journal-title":"Virulence"},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Roy, S., Santra, S., Das, A., Dixith, S., Sinha, M., Ghatak, S., Ghosh, N., Banerjee, P., Khanna, S., and Mathew-Steiner, S. (2019). Staphylococcus aureus biofilm infection compromises wound healing by causing deficiencies in granulation tissue collagen. Ann. Surg.","DOI":"10.1097\/SLA.0000000000003053"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1604","DOI":"10.1002\/jor.24291","article-title":"Large variations in clinical antibiotic activity against Staphylococcus aureus biofilms of periprosthetic joint infection isolates","volume":"37","author":"Mandell","year":"2019","journal-title":"J. Orthop. Res."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"374","DOI":"10.1016\/j.ijantimicag.2008.08.029","article-title":"Comparison of biofilm-associated cell survival following in vitro exposure of meticillin-resistant Staphylococcus aureus biofilms to the antibiotics clindamycin, daptomycin, linezolid, tigecycline and vancomycin","volume":"33","author":"Smith","year":"2009","journal-title":"Int. J. Antimicrob. Agents"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"742","DOI":"10.3389\/fchem.2019.00742","article-title":"Small molecule anti-biofilm agents developed on the basis of mechanistic understanding of biofilm formation","volume":"7","author":"Qvortrup","year":"2019","journal-title":"Front. Chem."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"3128","DOI":"10.1016\/j.bmc.2012.01.048","article-title":"Mapping pilicide anti-virulence effect in Escherichia coli, a comprehensive structure-activity study","volume":"20","author":"Chorell","year":"2012","journal-title":"Bioorg. Med. Chem."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"W257","DOI":"10.1093\/nar\/gky318","article-title":"ProTox-II: A webserver for the prediction of toxicity of chemicals","volume":"46","author":"Banerjee","year":"2018","journal-title":"Nucleic Acids Res."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"4066","DOI":"10.1021\/acs.jmedchem.5b00104","article-title":"pkCSM: Predicting small-molecule pharmacokinetic and toxicity properties using graph-based signatures","volume":"58","author":"Pires","year":"2015","journal-title":"J. Med. Chem."},{"key":"ref_36","first-page":"1","article-title":"The why and how of absorption, distribution, metabolism, excretion, and toxicity research","volume":"5","author":"Testa","year":"2007","journal-title":"Compr. Med. Chem. II"},{"key":"ref_37","unstructured":"CLSI (2019). M100 Performance Standards for Antimicrobial Susceptibility Testing, CLSI. [29th ed.]. M100."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"485","DOI":"10.1093\/jac\/dkn513","article-title":"Impact of biofilm on the in vitro activity of vancomycin alone and in combination with tigecycline and rifampicin against Staphylococcus aureus","volume":"63","author":"Rose","year":"2009","journal-title":"J. Antimicrob. Chemother."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1034","DOI":"10.3349\/ymj.2016.57.4.1034","article-title":"In Vitro activity of tigecycline against Orientia tsutsugamushi","volume":"57","author":"Lee","year":"2016","journal-title":"Yonsei Med. J."},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Sachdeva, R., Darbinian, N., Khalili, K., Amini, S., Gonzalez, D., Djeghader, A., Chabriere, E., Suh, A., Scott, K., and Simm, M. (2013). DING proteins from phylogenetically different species share high degrees of sequence and structure homology and block transcription of HIV-1 LTR promoter. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0069623"},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"O\u2019Toole, G.A. (2011). Microtiter dish biofilm formation assay. J. Vis. Exp.","DOI":"10.3791\/2437-v"}],"container-title":["Antibiotics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2079-6382\/9\/9\/612\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T10:10:48Z","timestamp":1760177448000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2079-6382\/9\/9\/612"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,9,17]]},"references-count":41,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2020,9]]}},"alternative-id":["antibiotics9090612"],"URL":"https:\/\/doi.org\/10.3390\/antibiotics9090612","relation":{},"ISSN":["2079-6382"],"issn-type":[{"value":"2079-6382","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,9,17]]}}}