Synergistic antibacterial effect of statins with the complex {[1-(4-bromophenyl)-3-phenyltriazene N 3 -oxide-κ 2 N 1 ,O 4 ](dimethylbenzylamine-κ 2 C 1 ,N 4 )palladium(II)}

Rampelotto, Roberta Filipini; Lorenzoni, Vinicius Victor; Silva, Danielly da Costa; Moraes, Guilherme A. de; Serafin, Marissa Bolson; Tizotti, Maísa Kräulish; Coelho, Silvana; Zambiazi, Priscilla; Hörner, Manfredo; Hörner, Rosmari

doi:10.1590/s2175-97902018000217369

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Brazilian Journal of Pharmaceutical Sciences

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Article • Braz. J. Pharm. Sci. 54 (02) • 2018 • https://doi.org/10.1590/s2175-97902018000217369 copy

Synergistic antibacterial effect of statins with the complex {[1-(4-bromophenyl)-3-phenyltriazene N ₃ -oxide-κ ² N ¹ ,O ⁴ ](dimethylbenzylamine-κ ² C ¹ ,N ⁴ )palladium(II)}

Authorship SCIMAGO INSTITUTIONS RANKINGS

Abstract

The treatment of infections caused by resistant microorganisms represents a big challenge in healthcare due to limited treatment options. For this reason, the discovery of new active substances which are able to perform innovative and selective actions is of great impact nowadays. Statins and triazenes (TZC) have consolidated as a promising class of compounds, characterized by the expressive biological activity, especially antimicrobial activities. The aim of this study was to assess the in vitro synergistic antibacterial effect of the association of statins and a new TZC complex {[1-(4-bromophenyl)-3-phenyltriazene N ₃-oxide-κ ² N ¹,O ⁴](dimethylbenzylamine-κ ² C ¹,N ⁴)palladium(II)} (Pd(DMBA)LBr) against American Type Culture Collection (ATCC) strains and clinical isolates. The complex and the statins showed bacterial activity of all tested strains and clinical isolates, evidencing that TZC complexion with metals can be promising. Simvastatin showed synergy when associated to the complex (FICI≤0.5), being the minimum inhibitory concentration (MIC) of 16 µg mL^-1 found in 6 samples. Thus, it is possible to infer that the association between Pd(DMBA)LBr and simvastatin consists of an alternative to increase the pontential of these compounds, since statins have low toxicity.

Keywords:
Statins/antimicrobial activity; Triazenide; Atorvastatin; Simvastatin.

Microorganism				µg mL^-1
Microorganism	A	S	L₁	L₁ + A	FICI	L₁ +S	FICI	L₂	L₂ +A	FICI	L₂ +S	FICI	P	P+A	FICI	P+S	FICI	C	C+A	FICI	C+S	FICI	Pd livre	Tig
Bacillus cereus ATCC 14579	256	256	256	128	1	64	0.5	128	128	1.5	32	0.4	256	128	1	64	0.5	64	64	1.3	32	0.6	256	*
Enterobacter hormaechei ATCC 700323	256	128	256	256	2	128	1.5	256	256	2	128	1.5	256	128	1	64	0.8	128	128	1.5	64	1	128	*
Enterococcus casseliflavus ATCC 700327	512	256	128	128	1.3	64	0.8	128	128	1.3	64	0.8	128	128	1.3	64	0.8	128	128	1.3	32	0.4	256	<0.25
Enterococcus faecalis ATCC 29212	256	64	256	256	2	128	2.5	256	128	1	32	0.6	256	128	1	32	0.6	128	128	1.5	32	0.8	256	<0.25
Enterococcus faecalis ATCC 51299	256	128	256	128	1	32	0.4	64	64	1.3	16	0.4	128	64	0.8	32	0.5	32	32	1.1	16	0.6	256	<0.25
Escherichia coli ATCC 25922	512	256	256	256	1.5	128	1	256	256	1.5	128	1	256	256	1,5	128	1	256	128	0.8	64	0.5	256	<0.25
Escherichia coli ATCC 35218	512	256	256	256	1.5	128	1	256	256	1.5	128	1	256	256	1.5	128	1	256	256	1.5	128	1	256	<0.25
Klebsiella pneumoniae ATCC 700603	256	128	256	256	2	128	1.5	256	256	2	128	1.5	256	128	1	64	0.8	128	128	1.5	64	1	256	0.5
Micrococcus luteus 7468	256	32	128	128	1.5	64	2.5	256	256	2	128	4.5	128	128	1.5	64	2.5	128	128	1.5	64	2.5	256	<0.25
Pseudomonas aeruginosa ATCC 27853	256	128	128	128	1.5	64	1	128	128	1.5	64	1	128	128	1.5	64	1	128	64	0.8	32	0.5	256	2
Salmonella typhimurium ATCC 14028	256	128	256	256	2	128	1.5	128	128	1.5	64	1	256	128	1	64	0.8	128	128	1.5	64	1	128	<0.25
Salmonella ATCC 52117	512	256	256	256	1,5	128	1	256	128	0.8	64	0.5	256	128	0.8	64	0.5	128	128	1.3	64	0.8	256	*
Staphylococcus aureus ATCC 25923	512	256	256	128	0.8	64	0.5	128	64	0.6	16	0.2	256	128	0.8	64	0.5	64	64	1.1	32	0.6	256	<0.25
Staphylococcus aureus 29213	512	256	512	256	1	32	0.2	256	128	0.8	32	0.3	256	128	0.8	32	0.3	128	128	1.3	16	0.2	512	<0.25
Staphylococcus aureus BAA 1026	256	128	256	256	2	32	0.4	256	128	1	32	0.4	256	128	1	32	0.4	128	128	1.5	16	0.3	256	<0.25
Staphylococcus aureus BAA 976	512	16	512	512	2	128	8.3	512	256	1	128	8.3	512	128	0.5	64	4.1	256	256	1.5	128	8.5	256	<0.25
Staphylococcus aureus BAA 977	256	32	512	256	1.5	128	4.3	256	256	2	128	4.5	512	256	1.5	128	4.3	128	128	1.5	32	1.3	256	<0.25
Staphylococcus epidermidis ATCC 12228	256	128	512	128	0.8	64	0.6	256	256	2	128	1.5	512	256	1.5	64	0.6	128	128	1.5	64	1	256	<0.25

Universidade de São Paulo, Faculdade de Ciências Farmacêuticas Av. Prof. Lineu Prestes, n. 580, 05508-000 S. Paulo/SP Brasil, Tel.: (55 11) 3091-3824 - São Paulo - SP - Brazil
E-mail: bjps@usp.br

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[1] *Correspondence: R. Hörner. Departamento de Análises Clínicas e Toxicológicas (DACT), Centro de Ciências da Saúde (CCS), Universidade Federal de Santa Maria (UFSM). Avenida Roraima, número 1000 - Prédio 26 - salas 1201/1205, CEP: 97105-900 - Santa Maria, Rio Grande do Sul, Brasil. Fone: 55 3220 8751 - FAX: 55 3220 1880. E-mail: rosmari.ufsm@gmail.com

Micro- organism	µg mL^-1
Micro- organism	A	S	L₁	L₁+ A	FICI	L₁+S	FICI	L₂	L₂+A	FICI	L₂+S	FICI	P	P+A	FICI	P+S	FICI	C	C+A	FICI	C+S	FICI	Pd livre
Isolate 1	256	128	512	256	1.5	64	0.6	256	256	2	64	0.8	256	256	2	64	0.8	128	128	1.5	32	0.5	256
Isolate 2	256	128	256	256	2	64	0.8	128	128	1.5	64	1	256	128	1	32	0.4	64	64	1.25	16	0.4	256
Isolate 3	256	128	256	256	2	64	0.8	128	128	1.5	64	1	256	128	1	64	0.8	64	64	1.25	16	0.4	256
Isolate 4	256	128	256	128	1	128	1.5	256	128	1	32	0.4	256	128	1	128	1.5	128	128	1.5	32	0.5	256
Isolate 5	128	64	128	128	2	64	1.5	128	128	2	32	0.8	128	128	2	64	1.5	64	64	1.5	16	0.5	256
Isolate 6	256	128	256	256	2	128	1.5	128	128	1.5	32	0.5	128	128	1.5	128	2	64	64	1.25	16	0.4	256
Isolate 7	128	64	256	256	3	32	0.6	128	128	2	32	0.8	256	128	1.5	64	1.3	64	64	1.5	16	0.5	256
Isolate 8	128	32	128	128	2	32	1.3	128	128	2	64	2.5	128	128	2	64	2.5	64	64	1.5	16	0.8	256
Isolate 9	256	128	512	256	1.5	64	0.6	128	128	1.5	64	1	256	128	1	64	0.8	64	64	1.25	32	0.8	256
Isolate 10	128	64	128	128	2	64	1,5	128	128	2	64	1.5	128	128	2	64	1.5	64	64	1.5	32	1	256
MIC⁵⁰	256	128	256	256	-	64	-	128	128	-	64	-	256	128	-	64	-	64	64	-	16	-	256
MIC₉₀	256	128	512	256	-	128	-	256	128	-	64	-	256	128	-	128	-	128	128	-	32	-	256