Cleavable Cationic Antibacterial Amphiphiles: Synthesis, Mechanism of Action, and Cytotoxicities

Abstract

The development of novel antimicrobial agents having high selectivity toward bacterial cells over mammalian cells is urgently required to curb the widespread emergence of infectious diseases caused by pathogenic bacteria. Toward this end, we have developed a set of cationic dimeric amphiphiles (bearing cleavable amide linkages between the headgroup and the hydrocarbon tail with different methylene spacers) that showed high antibacterial activity against human pathogenic bacteria (Escherichia coli and Staphylococcus aureus) and low cytotoxicity. The Minimum Inhibitory Concentrations (MIC) were found to be very low for the dimeric amphiphiles and were lower or comparable to the monomeric counterpart. In the case of dimeric amphiphiles, MIC was found to decrease with the increase in the spacer chain length (n = 2 to 6) and again to increase at higher spacer length (n > 6). It was found that the compound with six methylene spacers was the most active among all of the amphiphiles (MICs = 10-13 μM). By fluorescence spectroscopy, fluorescence microscopy, and field-emission scanning electron microscopy (FESEM), it was revealed that these cationic amphiphiles interact with the negatively charged bacterial cell membrane and disrupt the membrane integrity, thus killing the bacteria. All of the cationic amphiphiles showed low hemolytic activity (HC(50)) and high selectivity against both gram-positive and gram-negative bacteria. The most active amphiphile (n = 6) had a 10-13-fold higher HC(50) than did the MIC. Also, this amphiphile did not show any cytotoxicity against mammalian cells (HeLa cells) even at a concentration above the MIC (20 μM). The critical micellar concentration (CMC) values of gemini surfactants were found to be very low (CMC = 0.30-0.11 mM) and were 10-27 times smaller than the corresponding monomeric analogue (CMC = 2.9 mM). Chemical hydrolysis and thermogravimetric analysis (TGA) proved that these amphiphiles are quite stable under both acidic and thermal conditions. Collectively, these properties make the newly synthesized amphiphiles potentially superior disinfectants and antiseptics for various biomedical and biotechnological applications.

Synthesis and structure–activity relationship of novel 1,4-diazabicyclo[2.2.2]octane derivatives as potent antimicrobial agents

“…The outer wall and inner membrane of bacteria contain a higher number of charged phospholipids than eukaryotic membranes. Due to this fact the cationic compounds interact more selectively with bacterial membrane [14]. It explains the observed low mammalian toxicity of QACs [1].…”

“…Many works have shown that the spacer plays an important role in physical properties of the cationic compounds (e.g. micellization) and consequently in their biological activity [14,27]. The spacer can vary in length and chemical structure and obtains M A N U S C R I P T A C C E P T E D ACCEPTED MANUSCRIPT 4 different properties (flexibility or rigidity; hydrophobicity or hydrophility).…”

Self-assembling systems based on quaternized derivatives of 1,4-diazabicyclo[2.2.2]octane in nutrient broth as antimicrobial agents and carriers for hydrophobic drugs

“…This fundamental property of surfactants resulting from their amphiphilic nature has received much attention in recent papers [6,7]. In aqueous media, the so-called direct micelles the bacterial cells, diffusion through the cell wall, and disruption of cytoplasmic membrane [27]; and (ii) the investigation of new effective agents, which is motivated by the increasing resistance of microorganisms [28,29]. To answer the criteria of green chemistry, different types of cationic [8,[30][31][32][33][34][35] and nonionic [36] surfactants of lower toxicity have been designed, among which ionic liquids [31,32] and surfactants bearing natural fragments [33][34][35] are reported.…”

Structure-antimicrobial activity relationship and action mechanism of dimeric quaternary ammonium amphiphiles

“…Among numerous antimicrobial agents, small-molecular-weight quaternary ammonium compounds (QACs) are extensively used as antimicrobial agents because of wide spectrum of antimicrobial activity against bacteria (both gram positive and gram negative), fungi, and certain viruses [3][4][5] . Dimeric amphiphiles, which are composed of two hydrophobic quaternary ammonium head groups and two hydrophilic chains, appear to be much better antibacterial activity than the corresponding conventional mono-QACs [6][7] . Among various types of dimeric amphiphiles, the set of dicationic quaternary ammonium compounds (often expressed as m-s-m, where m and s denote the numbers of carbon atoms in the free alkyl chains and the spacer, respectively) have been probably the most widely studied [8][9] , but a complete understanding of structure-antimicrobial activity relationship and the action mechanism for these dimeric amphiphiles are still lacking.…”