Abstract
We previously synthesized several series of compounds, based on the 5-aryl-2-aminoimidazole scaffold, that showed activity preventing the formation of Salmonella enterica serovar Typhimurium and Pseudomonas aeruginosa biofilms. Here, we further studied the activity spectrum of a number of the most active N1- and 2N-substituted 5-aryl-2-aminoimidazoles against a broad panel of biofilms formed by monospecies and mixed species of bacteria and fungi. An N1-substituted compound showed very strong activity against the biofilms formed by Gram-negative and Gram-positive bacteria and the fungus Candida albicans but was previously shown to be toxic against various eukaryotic cell lines. In contrast, 2N-substituted compounds were nontoxic and active against biofilms formed by Gram-negative bacteria and C. albicans but had reduced activity against biofilms formed by Gram-positive bacteria. In an attempt to develop nontoxic compounds with potent activity against biofilms formed by Gram-positive bacteria for application in antibiofilm coatings for medical implants, we synthesized novel compounds with substituents at both the N1 and 2N positions and tested these compounds for antibiofilm activity and toxicity. Interestingly, most of these N1-,2N-disubstituted 5-aryl-2-aminoimidazoles showed very strong activity against biofilms formed by Gram-positive bacteria and C. albicans in various setups with biofilms formed by monospecies and mixed species but lost activity against biofilms formed by Gram-negative bacteria. In light of application of these compounds as anti-infective coatings on orthopedic implants, toxicity against two bone cell lines and the functionality of these cells were tested. The N1-,2N-disubstituted 5-aryl-2-aminoimidazoles in general did not affect the viability of bone cells and even induced calcium deposition. This indicates that modulating the substitution pattern on positions N1 and 2N of the 5-aryl-2-aminoimidazole scaffold allows fine-tuning of both the antibiofilm activity spectrum and toxicity.
Highlights
We previously synthesized several series of compounds, based on the 5-aryl-2-aminoimidazole scaffold, that showed activity preventing the formation of Salmonella enterica serovar Typhimurium and Pseudomonas aeruginosa biofilms
The three reference compounds were chosen on the basis of their previously reported preventive, biofilm-specific activity, toxicity, and commercial availability: (i) baicalein at 20 M inhibits biofilm formation of P. aeruginosa PAO1 [82], whereas biofilm formation of C. albicans SC5314 is inhibited by 10 to 100 M baicalein [83]; (ii) nifuroxazide inhibits P. aeruginosa PAO1 biofilm formation at 70 M [84]; and (iii) tannic acid inhibits the biofilm formation of S. aureus SH1000, E. coli VR50, and E. coli F18 at 20 M [85, 86]
We found that baicalein displayed antibiofilm activity against E. coli (BIC50, 1.2 M) and to a lesser extent against B. cepacia (BIC50, 48.9 M)
Summary
We previously synthesized several series of compounds, based on the 5-aryl-2-aminoimidazole scaffold, that showed activity preventing the formation of Salmonella enterica serovar Typhimurium and Pseudomonas aeruginosa biofilms. These series include the monosubstituted 5-aryl-2-AIs (5-Ar-2-AIs) [26], N1-substituted 5-Ar-2-AIs [26], 2N-substituted 5-Ar-2-AIs [27], 4,5-disubstituted 2-AIs [26], 1,4,5-trisubstituted 2-AIs [28], and 2-AI–triazole conjugates [29] These compounds were shown to display activity preventing the formation of biofilms of Salmonella enterica serovar Typhimurium, one of the most important causes of foodborne infections worldwide and a notorious biofilm former both inside and outside the host, and of Pseudomonas aeruginosa, an opportunistic Gramnegative bacterial pathogen that can infect immunocompromised people, such as cystic fibrosis patients, and cause life-threatening chronic lung infections [30]. This indicates that under the influence of the compound, Salmonella forms fewer biofilm matrix components, thereby at least partly explaining the inhibitory mode of action of the 2-aminoimidazoles
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