Benzimidazolium salts prevent and disrupt methicillin-resistant Staphylococcus aureus biofilms

Abstract

Emergence of resistant bacteria encourages us to develop new antibiotics and strategies to compensate for the different mechanisms of resistance they acquire. One of the defense mechanisms of resistant bacteria is the formation of biofilms. Herein we show that benzimidazolium salts with various flexible or rigid side chains act as strong antibiotic and antibiofilm agents. We show that their antibiofilm activity is due to their capacity to destroy the biofilm matrix and the bacterial cellular membranes. These compounds are able to avoid the formation of biofilms and disperse mature biofilms showing a universal use in the treatment of biofilm-associated infections.

Fig. 1. Structure of benzimidazolium salts.

Scheme 1. Synthesis of second and third generation analogues.

Fig. 2. (Top) MRSA biofilms labeled with Live/Dead stains after a 12 h incubation at the MIC concentration of the antimicrobials. (1a) Negative control (DMSO); (1b) compound 6; (1c) compound 11; (1d) compound 14; (1e) compound 21; (bottom) SEM images of MRSA biofilms after a 12 h incubation with MIC concentration of the antimicrobials. (2a) Negative control (DMSO); (2b) compound 6; (2c) compound 11; (2d) compound 14; (2e) compound 21.

Fig. 3. (Top) MRSA biofilms labeled with Live/Dead stains after a 12 h incubation with MIC concentration of the antimicrobials. (1a) Negative control (DMSO); (1b) compound 34; (1c) compound 39; (1d) compound 42; (bottom) SEM images of MRSA biofilms after a 12 h incubation with MIC concentration of the antimicrobials. (2a) Negative control (DMSO); (2b) compound 34; (2c) compound 39; (2d) compound 42.

Fig. 4. Antibiofilm activity of studied compounds. Compared to commercially available BAC, all the benzimidazolium salts possess the ability to prevent the formation and disrupt mature biofilms. The dotted line represents the 25-fold selectivity towards MRSA bacteria compared to RBC.