Scaffold‐Hopping of Multicationic Amphiphiles Yields Three New Classes of Antimicrobials

Abstract

Quaternary ammonium compounds (QACs) are a vital class of antiseptics. Recent investigations into their construction are uncovering novel and potent multicationic variants. Based on a trisQAC precedent, we have implemented a scaffold-hopping approach to develop alternative QAC architectures that display 1-3 long alkyl chains in specific projections from cyclic and branched core structures bearing 3-4 nitrogen atoms. The preparation of 30 QAC structures allowed for correlation of scaffold structure with antimicrobial activity. We identified QACs with limited conformational flexibility that have improved bioactivity against planktonic bacteria as compared to their linear counterparts. We also confirmed that resistance, as evidenced by an increased minimum inhibitory concentration (MIC) for methicillin-resistant Staphylococcus aureus (MRSA) compared to methicillin-susceptible Staphylococcus aureus (MSSA), can reduce efficacy up to 64-fold for monocationic QACs. Differentiation of antimicrobial and anti-biofilm activity, however, was not observed, suggesting that these compounds utilize a non-specific mode of eradication.

Structure–Resistance Relationships: Interrogating Antiseptic Resistance in Bacteria with Multicationic Quaternary Ammonium Dyes

“…Marked differences in MIC values against the SA strains were observed for all monoQACs tested, which are bolded in Table 1. In fact, up to 125-fold increases in MIC values were noted (e.g.,T ET-14,0,0 and TET-16,0,0), even thought he most activec ompounds (e.g.,T ET-16,1,1) showed no differencei na ctivity.I nc omparison with other published results,m ulti-amine QAC scaffolds developed in our labs (N-, Q-, P-, C-, T-series) exhibited significantly less dramatic MIC changes (usually under 16-fold) when comparing SA and CA-MRSA, even when monocationic, [10][11][12][13][14] suggesting that the mul-Scheme1.Synthesis of mono-, bis-, and tris-quaternary ammonium compoundsb yalkylation of dye-based scaffolds.…”

“…In contrast, some of the most potent antiseptics developed in our lab are multicationic;t hese often exhibit low-micromolar concentrationsa gainst both Gram-positive and Gram-negative bacteria. [10][11][12][13][14][15] We thus sought to expand on thesee arlier findings,e xploring series of compounds with varied cationic character as well as aromatic groups,t oi nvestigate whether aryl substrates are indeed particularly prone to QacR recognition. We rationally designed al ibrary of QACs featuring dye scaffolds known to permeate cellular membranes, taking advantage of the reported QacR binding of crystal violet and malachite green.…”

An Investigation into Rigidity–Activity Relationships in BisQAC Amphiphilic Antiseptics

“…[9] Other structural phenomena investigated have been the presence of anionic analogs, [10] polymeric scaffolds, [11] separation of charged groups, [12] and oftentimes the importance of scaffold structure. [13] Our own work initially pushed towards the inclusion of multiple (up to 4) cationic groups, [14] although subsequent data indicated the diminishing advantages of cations beyond the first two. [15] We have thus pivoted to eye molecular geometry, [8a] based on the logic that both cationic presentation to the net anionic bacterial cell membrane is important for Coulombic attachment, and that non-polar groups must subsequently intercalate into the bacterial membrane to trigger disruption.…”

Building a Better Quaternary Ammonium Compound (QAC): Branched Tetracationic Antiseptic Amphiphiles

“…[10,11] Still others have focused on the designo f" soft" amphiphiles, which incorporateh ydrolyzable bondst hat may decrease toxicity due to their ability to be readily metabolized. [12][13][14] Such QACs typicallyd isplay equipotent activity to their non-hydrolyzable counterparts, while degradinga fter af ew hours to af ew days.O ur laboratories have likewise endeavored to advance our QACc apacities, investigating av ariety of bis-and multiQAC structures; [15][16][17][18][19][20] ar eview of our efforts has recently been reported. [21] Common themes have emerged-optimal alkyl chain lengths are generally~12 carbons, and the incorporation of at least two ammonium cations generally leads to an increase in antimicrobiala ctivity,a s well as significant biofilm eradication capability.MultiQACs also show the promise to address bacterial resistance;whereas bacteria bearing genes for key efflux pumps show increased tolerance toward many commerciallya vailable QACs, resistantb acteria are seemingly thwarted in mostc ases by multicationic systems.…”