Abstract
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.
Highlights
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 [1,2,3,4,5,6,7].The important clinical S. aureus infections are bacteraemia, infective endocarditis, as well as skin and softMolecules 2020, 25, 2302; doi:10.3390/molecules25102302 www.mdpi.com/journal/moleculesMolecules 2020, 25, 2302 tissue, osteoarticular, pleuropulmonary, and device-related infections
For these experiments four 4-arylthiosemicarbazides were included for comparison, whereas amoxicillin, gentamicin, levofloxacin, linezolid, and vancomycin were selected to represent the five antimicrobial classes most commonly used in clinical practice
The most promising antibacterial agents that emerged from our studies on antibacterial potency of thiosemicarbazides [20,21,23,25,26] are those with 4-benzoyl-1-(2,3-dichlorobenzoyl) thiosemicarbazide scaffold
Summary
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 [1,2,3,4,5,6,7].The important clinical S. aureus infections are bacteraemia, infective endocarditis, as well as skin and softMolecules 2020, 25, 2302; doi:10.3390/molecules25102302 www.mdpi.com/journal/moleculesMolecules 2020, 25, 2302 tissue, osteoarticular, pleuropulmonary, and device-related infections. 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 [1,2,3,4,5,6,7]. S. aureus deploys a specific combinations of virulence factors, such as adhesins, toxins, and immunomodulatory molecules, that facilitate infection of host tissues and evading from host immune response [10,11]. The ability to resist the activity of multiple antibiotics classes makes S. aureus difficult to treat. Over decades, S. aureus isolates have developed resistance to several classes of antibiotics, like β-lactams, fluoroquinolones, macrolides, glycopeptides, and oxazolidinones [12,13]
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