{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,12]],"date-time":"2026-07-12T04:50:50Z","timestamp":1783831850069,"version":"3.55.0"},"reference-count":41,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2020,5,14]],"date-time":"2020-05-14T00:00:00Z","timestamp":1589414400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Antimicrobial resistance spurred by the overuse and misuse of antibiotics is a major global health concern, and of the Gram positive bacteria, S. aureus is a leading cause of mortality and morbidity. Alternative strategies to treat S. aureus infections, such as combination therapy, are urgently needed. In this study, a checkerboard method was used to evaluate synergistic interactions between nine thiosemicarbazides (4-benzoyl-1-(2,3-dichloro-benzoyl)thiosemicarbazides 1\u20135 and 4-aryl-1-(2-fluorobenzoyl)thiosemicarbazides 6\u20139) and conventional antibiotics against S. aureus ATCC 25923, which were determined as the fractional inhibitory concentration indices (FICIs). For these experiments, amoxicillin, gentamicin, levofloxacin, linezolid, and vancomycin were selected to represent the five antimicrobial classes most commonly used in clinical practice. With one exception of 7-vancomycin combination, none of the forty-five thiosemicarbazide-antibiotic combinations tested had an antagonistic effect, showing promising results with respect to a combination therapy. The synergic effect was observed for the 2-linezolid, 4-levofloxacin, 5-linezolid, 6-gentamicin, 6-linezolid, and 7-levofloxacin combinations. No interactions were seen in combination of the thiosemicarbazide with gentamicin or vancomycin, whereas all combinations with linezolid acted in additive or synergism, except for 6-gentamicin and 7-linezolid. The 4-(4-chlorophenyl)-1-(2-fluorobenzoyl)thiosemicarbazide 6 showed a clear preference for the potency; it affected synergistically in combinations with gentamicin or linezolid and additively in combinations with amoxicillin, levofloxacin, or vancomycin. In further studies, the inhibitory potency of the thiosemicarbazides against S. aureus DNA gyrase and topoisomerase IV was examined to clarify the molecular mechanism involved in their synergistic effect in combination with levofloxacin. The most potent synergist 6 at concentration of 100 \u00b5M was able to inhibit ~50% activity of S. aureus DNA gyrase, thereby suggesting that its anti-gyrase activity, although weak, may be a possible factor contributing to its synergism effect in combination with linezolid or gentamycin.<\/jats:p>","DOI":"10.3390\/molecules25102302","type":"journal-article","created":{"date-parts":[[2020,5,14]],"date-time":"2020-05-14T10:27:19Z","timestamp":1589452039000},"page":"2302","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Synergistic Effects of Thiosemicarbazides with Clinical Drugs against S. aureus"],"prefix":"10.3390","volume":"25","author":[{"given":"Beata","family":"Chudzik-Rz\u0105d","sequence":"first","affiliation":[{"name":"Department of Pharmaceutical Microbiology with Laboratory for Microbiological Diagnostics, Faculty of Pharmacy, Medical University of Lublin, Chod\u017aki 1, 20-093 Lublin, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1503-7634","authenticated-orcid":false,"given":"Anna","family":"Malm","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Microbiology with Laboratory for Microbiological Diagnostics, Faculty of Pharmacy, Medical University of Lublin, Chod\u017aki 1, 20-093 Lublin, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8817-7470","authenticated-orcid":false,"given":"Nazar","family":"Trotsko","sequence":"additional","affiliation":[{"name":"Department of Organic Chemistry, Faculty of Pharmacy, Medical University of Lublin, Chodzki 4a, 20-093 Lublin, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9816-1934","authenticated-orcid":false,"given":"Monika","family":"Wujec","sequence":"additional","affiliation":[{"name":"Department of Organic Chemistry, Faculty of Pharmacy, Medical University of Lublin, Chodzki 4a, 20-093 Lublin, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8162-8435","authenticated-orcid":false,"given":"Tomasz","family":"Plech","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Faculty of Health Sciences, Medical University of Lublin, Chod\u017aki 4a, 20-093 Lublin, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8198-7702","authenticated-orcid":false,"given":"Agata","family":"Paneth","sequence":"additional","affiliation":[{"name":"Department of Organic Chemistry, Faculty of Pharmacy, Medical University of Lublin, Chodzki 4a, 20-093 Lublin, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,5,14]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"336","DOI":"10.1038\/nature17042","article-title":"Antibacterial drug discovery in the resistance era","volume":"529","author":"Brown","year":"2016","journal-title":"Nature"},{"key":"ref_2","unstructured":"(2020, January 02). 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