The antibacterial activity of 4,4′-bipyridinium amphiphiles with conventional, bicephalic and gemini architectures

Grenier, Melissa C.; Davis, Robert W.; Wilson-Henjum, Kelsey L.; LaDow, Jade E.; Black, Jacob W.; Caran, Kevin L.; Seifert, Kyle; Minbiole, Kevin P. C.

doi:10.1016/j.bmcl.2012.04.079

Cited by 50 publications

(39 citation statements)

References 23 publications

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“…MIC variation mostly hinged on the length of alkyl chain, where the dodecyl chain was generally found to be optimal, in line with our previous observations. [13][14][15][16] To our surprise, however, the number of cations or basic nitrogens present in the amphiphile was not a key determinant of bioactivity. This was exemplified in the comparison of the X = CH 2 compounds, in both the n,5,n series (1-4) as well as 12,7,12 (20), to the corresponding structures bearing the N-CH 3 group (5, 7-9, 21) or quaternary ammonium groups (10, 12-13, 22, etc.…”

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confidence: 98%

“…We have developed quaternary ammonium amphiphiles based on an all-carbon aromatic core (A), 13 an inexpensive TMEDA core (B), 14 as well as bis-pyridinium structures of both 4,4 0 (C) 15 and other geometries (D), 16 as illustrated in Figure 1. Encouraged by both the precedent of the Falkinham/Gandour polyanionic compounds, as well as the knowledge that bacterial membranes display a significantly anionic surface, we decided to investigate the effect of additional cationic moieties on bioactivity.…”

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confidence: 99%

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The antimicrobial activity of mono-, bis-, tris-, and tetracationic amphiphiles derived from simple polyamine platforms

Paniak

Jennings

Shanahan

et al. 2014

Bioorganic & Medicinal Chemistry Letters

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confidence: 98%

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confidence: 99%

The antimicrobial activity of mono-, bis-, tris-, and tetracationic amphiphiles derived from simple polyamine platforms

Paniak

Jennings

Shanahan

et al. 2014

Bioorganic & Medicinal Chemistry Letters

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“…[31,32] As PQs are bis-cationic compounds with delocalized charges, we hypothesized that these compounds would also be potent anti-biofilm agents. Indeed, compound 8, the lead antimicrobial PQ, is one of the most potent compounds to date, with MBEC values of 50 mm against both bacteria evaluated in this study.…”

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confidence: 99%

Biofilm‐Eradicating Properties of Quaternary Ammonium Amphiphiles: Simple Mimics of Antimicrobial Peptides

et al. 2014

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Bacterial biofilms are difficult to eradicate because of reduced antibiotic sensitivity and altered metabolic processes; thus, the development of new approaches to biofilm eradication is urgently needed. Antimicrobial peptides (AMPs) and quaternary ammonium cations (QACs) are distinct, yet well-known, classes of antibacterial compounds. By mapping the general regions of charge and hydrophobicity of QACs onto AMP structures, we designed a small library of QACs to serve as simple AMP mimics. In order to explore the role that cationic charge plays in biofilm eradication, structures were varied with respect to cationic character, distribution of charge, and alkyl side chain. The reported compounds possess minimum biofilm eradication concentrations (MBEC) as low as 25 μM against Gram-positive biofilms, making them the most active anti-biofilm structures reported to date. These potent AMP mimics were synthesized in 1-2 steps and hint at the minimal structural requirements for biofilm destruction.

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“…The MIC then increases for amphiphiles with tail lengths exceeding this optimal length. [14][15][16][17][18][19][20][21] Variations in spacing between head groups can also impact the MIC. For example, studies conducted by our labs show that amphiphiles with a 5-carbon spacer between two cationic head groups are the most biologically active.…”

Section: Introductionmentioning

confidence: 99%

“…13 A large variety of novel amphiphiles has been synthesized in an effort to increase effectiveness and specificity. [14][15][16][17][18][19][20][21][22][23][24] Amphiphile structure, including size and relative number of hydrophobic tails and hydrophilic head groups, governs colloidal characteristics including the critical aggregation concentration (CAC) and thermodynamic properties. 25 At concentrations below the CAC, amphiphiles tend to align at the air-water interface in equilibrium with dissolved monomers in solution.…”

Section: Introductionmentioning

confidence: 99%

Colloidal and antibacterial properties of novel triple-headed, double-tailed amphiphiles: Exploring structure–activity relationships and synergistic mixtures

Marafino

Gallagher

Barragan

et al. 2015

Bioorganic & Medicinal Chemistry

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Two novel series of tris-cationic, tripled-headed, double-tailed amphiphiles were synthesized and the effects of tail length and head group composition on the critical aggregation concentration (CAC), thermodynamic parameters, and minimum inhibitory concentration (MIC) against six bacterial strains were investigated. Synergistic antibacterial combinations of these amphiphiles were also identified. Amphiphiles in this study are composed of a benzene core with three benzylic ammonium bromide groups, two of which have alkyl chains, each 8-16 carbons in length. The third head group is a trimethylammonium or pyridinium. Log of critical aggregation concentration (log[CAC]) and heat of aggregation (ΔHagg) were both inversely proportional to the length of the linear hydrocarbon chains. Antibacterial activity increases with tail length until an optimal tail length of 12 carbons per chain, above which, activity decreased. The derivatives with two 12 carbon chains had the best antibacterial activity, killing all tested strains at concentrations of 1-2μM for Gram-positive and 4-16μM for Gram-negative bacteria. The identity of the third head group (trimethylammonium or pyridinium) had minimal effect on colloidal and antibacterial activity. The antibacterial activity of several binary combinations of amphiphiles from this study was higher than activity of individual amphiphiles, indicating that these combinations are synergistic. These amphiphiles show promise as novel antibacterial agents that could be used in a variety of applications.

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The antibacterial activity of 4,4′-bipyridinium amphiphiles with conventional, bicephalic and gemini architectures

Cited by 50 publications

References 23 publications

The antimicrobial activity of mono-, bis-, tris-, and tetracationic amphiphiles derived from simple polyamine platforms

The antimicrobial activity of mono-, bis-, tris-, and tetracationic amphiphiles derived from simple polyamine platforms

Biofilm‐Eradicating Properties of Quaternary Ammonium Amphiphiles: Simple Mimics of Antimicrobial Peptides

Colloidal and antibacterial properties of novel triple-headed, double-tailed amphiphiles: Exploring structure–activity relationships and synergistic mixtures

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