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Scaffold‐Hopping of Multicationic Amphiphiles Yields Three New Classes of Antimicrobials
Author(s) -
Mitchell Myles A.,
Iannetta Anthony A.,
Jennings Megan C.,
Fletcher Madison H.,
Wuest William M.,
Minbiole Kevin P. C.
Publication year - 2015
Publication title -
chembiochem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.05
H-Index - 126
eISSN - 1439-7633
pISSN - 1439-4227
DOI - 10.1002/cbic.201500381
Subject(s) - antimicrobial , scaffold , staphylococcus aureus , amphiphile , biofilm , bacteria , ammonium , chemistry , methicillin resistant staphylococcus aureus , combinatorial chemistry , flexibility (engineering) , alkyl , microbiology and biotechnology , structure–activity relationship , biophysics , biochemistry , biology , organic chemistry , copolymer , in vitro , polymer , biomedical engineering , medicine , genetics , statistics , mathematics
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.