Antibacterial and Antibiofilm Activity of Cationic Small Molecules with Spatial Positioning of Hydrophobicity: An in Vitro and in Vivo Evaluation

Abstract

More than 80% of the bacterial infections are associated with biofilm formation. To combat infections, amphiphilic small molecules have been developed as promising antibiofilm agents. However, cytotoxicity of such molecules still remains a major problem. Herein we demonstrate a concept in which antibacterial versus cytotoxic activities of cationic small molecules are tuned by spatial positioning of hydrophobic moieties while keeping positive charges constant. Compared to the molecules with more pendent hydrophobicity from positive centers (MIC = 1-4 μg/mL and HC = 60-65 μg/mL), molecules with more confined hydrophobicity between two centers show similar antibacterial activity but significantly less toxicity toward human erythrocytes (MIC = 1-4 μg/mL and HC = 805-1242 μg/mL). Notably, the optimized molecule is shown to be nontoxic toward human cells (HEK 293) at a concentration at which it eradicates established bacterial biofilms. The molecule is also shown to eradicate preformed bacterial biofilm in vivo in a murine model of superficial skin infection.

Preparation of aminoalkyl‐grafted bacterial cellulose membranes with improved antimicrobial properties for biomedical applications

“…This indicated that some hydrophobic aminoalkylsilane groups were introduced on the structure of BC membranes. The surface wettability was reported to affect bacterial cell behaviors and materials with increased hydrophobicity showed enhanced antibacterial performance (Hoque, Konai, Sequeira, Samaddar, & Haldar, 2016).…”

Identification of GXXXXG motif in Chrysophsin-1 and its implication in the design of analogs with cell-selective antimicrobial and anti-endotoxin activities

“…The results indicated towards the importance of a helix breaker like proline in impairing the structural property of this motif in mammalian membrane mimetic environments. Since proline is the smallest amino acid lacking a side chain, any amino acid other than proline in place of glycine would have altered the hydrophobicity of the resulting analog which is an important attribute in antimicrobial peptides 21 . Moreover, glycine residue(s) have been replaced with proline residues earlier without causing much secondary structural changes 22, 23 .…”

Analysis of the Destabilization of Bacterial Membranes by Quaternary Ammonium Compounds: A Combined Experimental and Computational Study

“…Such insights may assist in the development of new generations of potent QACs, while mitigating the bacterial resistance involved with antiseptics. Importantly, several attempts had already been made in order to reduce the proliferation of bacterial resistance, particularly the development of “soft QACs” amphiphiles bearing cleavable side chains that hydrolyze into non‐potent residues . Both ester‐ and amide‐based side chains have been previously installed within a variety of QACs, as they allowed for faster decomposition in environmental settings (Figure ).…”