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Antibacterial activity of curcumin-cinnamaldehyde hybrids against planktonic cells and biofilms of MSSA and MRSA

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Beatriz de Carvalho Marques
Total Authors: 1
Document type: Master's Dissertation
Press: São José do Rio Preto. 2019-06-24.
Institution: Universidade Estadual Paulista (Unesp). Instituto de Biociências Letras e Ciências Exatas. São José do Rio Preto
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Advisor: Luis Octavio Regasini; Janaina de Cassia Orlandi Sardi

Staphylococcus aureus is a gram-positive, commensal and pathogenic bacteria that colonizes approximately 30% of the human population, presenting resistance to several antibiotics. Studies indicate the bioactivity of curcumin and cinnamaldehyde against S. aureus, however, both have limitations that prevent its use as a therapeutic agent. Thus, in order to optimize anti-S. aureus activity of curcumin and cinnamaldehyde, as well as its chemical-biological properties, in the present study, two series of curcumincinnamaldehyde hybrids were planned and synthesized and subsequently evaluated against methicillin-susceptible and methicillin-resistant S. aureus (MSSA and MRSA). The most active hybrid was selected for evaluation of its combination with antibiotics, and for its anti-adhesion activity, antibiofilm and the time kill of MSSA and MRSA. In vivo toxicity of this hybrid was also evaluated using the Galleria mellonella invertebrate. Hybrids were further evaluated for their antibacterial activity against other bacterial species and Mycobacterium tuberculosis, and investigated in silico for their drug-likeness properties. Thirty hybrids were obtained with purity between 86 and 100%, of which twelve were unpublished. In general, the molecular hybridization between curcumin and cinnamaldehyde maintained or increased the antibacterial activity of hybrids when compared to curcumin and cinnamaldehyde, and lipophilicity was a central parameter in bioactivity against MSSA and MRSA. Hybrid 20 showed more pronounced activity, presented Minimal Inhibitory Concentration (MIC) of 7.8 μg/mL and Minimum Bactericidal Concentration (MBC) of 15.6 μg/mL for MSSA, and MIC of 3.9 μg/mL and MBC of 7,8 μg/mL for MRSA, being selected for subsequent assays. Associations between 20 and vancomycin or methicillin increased the antibacterial activity against MSSA and MRSA. Treatment with 20 decreased the adherence of MSSA and MRSA strains onto human keratinocytes when compared to the untreated group. For biofilms, after treatment with 20, there was a decrease in their survival when compared to the negative control, presenting antibiofilm activity similar or superior to vancomycin and methicillin. In time kill assay, treatment with 20 decreased the bacterial population, indicating bactericidal action. In addition, 20 presented toxicity at 90 mg/kg, after 72 hours of treatment, being responsible for the death of 50% of G. mellonella. Against Enterococcus faecalis, Staphylococcus epidermidis and Pseudomonas aeruginosa, the more lipophilic hybrids demonstrated greater bioactivity. Hybrids showed no antibacterial activity against Escherichia coli. Acinetobacter baumannii was the bacterial species most susceptible to hybrids. Against Mycobacterium tuberculosis, it was found that the insertion of electron withdrawing and lipophilic groups increased the antimycobacterial activity. In relation to in silico studies, hybrids did not violate the rules established by Lipinski and Veber, corroborating good drug-likeness properties. In this study, we can prove the antibacterial activity of curcumin-cinnamaldehyde hybrids, stimulating the study of these substances, in order to find agents capable of acting against resistant strains. (AU)