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Synergistic Effects of Thiosemicarbazides with Clinical Drugs against S. aureus
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 need...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7288171/ https://www.ncbi.nlm.nih.gov/pubmed/32422899 http://dx.doi.org/10.3390/molecules25102302 |
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author | Chudzik-Rząd, Beata Malm, Anna Trotsko, Nazar Wujec, Monika Plech, Tomasz Paneth, Agata |
author_facet | Chudzik-Rząd, Beata Malm, Anna Trotsko, Nazar Wujec, Monika Plech, Tomasz Paneth, Agata |
author_sort | Chudzik-Rząd, Beata |
collection | PubMed |
description | 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 1–5 and 4-aryl-1-(2-fluorobenzoyl)thiosemicarbazides 6–9) 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 µM 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. |
format | Online Article Text |
id | pubmed-7288171 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-72881712020-06-17 Synergistic Effects of Thiosemicarbazides with Clinical Drugs against S. aureus Chudzik-Rząd, Beata Malm, Anna Trotsko, Nazar Wujec, Monika Plech, Tomasz Paneth, Agata Molecules Article 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 1–5 and 4-aryl-1-(2-fluorobenzoyl)thiosemicarbazides 6–9) 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 µM 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. MDPI 2020-05-14 /pmc/articles/PMC7288171/ /pubmed/32422899 http://dx.doi.org/10.3390/molecules25102302 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Chudzik-Rząd, Beata Malm, Anna Trotsko, Nazar Wujec, Monika Plech, Tomasz Paneth, Agata Synergistic Effects of Thiosemicarbazides with Clinical Drugs against S. aureus |
title | Synergistic Effects of Thiosemicarbazides with Clinical Drugs against S. aureus |
title_full | Synergistic Effects of Thiosemicarbazides with Clinical Drugs against S. aureus |
title_fullStr | Synergistic Effects of Thiosemicarbazides with Clinical Drugs against S. aureus |
title_full_unstemmed | Synergistic Effects of Thiosemicarbazides with Clinical Drugs against S. aureus |
title_short | Synergistic Effects of Thiosemicarbazides with Clinical Drugs against S. aureus |
title_sort | synergistic effects of thiosemicarbazides with clinical drugs against s. aureus |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7288171/ https://www.ncbi.nlm.nih.gov/pubmed/32422899 http://dx.doi.org/10.3390/molecules25102302 |
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