ACS Chem. Biol.All Publications/WebsiteOR SEARCH CITATIONS Recently ViewedYou have not visited any articles yet, Please visit some articles to see contents here. Received1 September 2013Accepted21 October 2013Published online1 November 2013Published inissue 17 January 2014https://doi.org/10.1021/cb4006613Copyright © 2013 American Chemical SocietyRIGHTS & PERMISSIONSArticle Views1624Altmetric-Citations50LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated.Get e-AlertsAbstractAntimicrobial peptides (AMPs) are host-defense agents capable of both bacterial membrane disruption and immunomodulation. However, the development of natural AMPs as potential therapeutics is hampered by their moderate activity and susceptibility to protease degradation. Herein we report lipidated cyclic γ-AApeptides that have potent antibacterial activity against clinically relevant Gram-positive and Gram-negative bacteria, many of which are resistant to conventional antibiotics. We show that lipidated cyclic γ-AApeptides mimic the bactericidal mechanism of AMPs by disrupting bacterial membranes. Interestingly, they also harness the immune response and inhibit lipopolysaccharide (LPS) activated Toll-like receptor 4 (TLR4) signaling, suggesting that lipidated cyclic γ-AApeptides have dual roles as novel antimicrobial and anti-inflammatory agents.Supporting InformationARTICLE SECTIONSJump ToStructures of lipidated cyclic γ-AApeptide building blocks, synthesis and structures of lipidated cyclic γ-AApeptides, toxicity of YL-36, MALDI analysis of lipidated cyclic γ-AApeptides, experimental methods, HPLC traces, and NMR data. This material is available free of charge via the Internet at http://pubs.acs.org.cb4006613_si_001.pdf (681.81 kb) Most electronic Supporting Information files are available without a subscription to ACS Web Editions. Such files may be downloaded by article for research use (if there is a public use license linked to the relevant article, that license may permit other uses). Permission may be obtained from ACS for other uses through requests via the RightsLink permission system: http://pubs.acs.org/page/copyright/permissions.html. Cited ByThis article is cited by 50 publications.Mi Zhou, Mengmeng Zheng, Jianfeng Cai. Small Molecules with Membrane-Active Antibacterial Activity. ACS Applied Materials Interfaces 2020, 12 (19) , 21292-21299. https://doi.org/10.1021/acsami.9b20161ChristineM. Artim, Joseph S. Brown, Christopher A. Alabi. Biophysical Characterization of Cationic Antibacterial Oligothioetheramides. Analytical Chemistry 2019, 91 , 3118-3124. https://doi.org/10.1021/acs.analchem.8b05721ChristineM. Artim, Ngoc N. Phan, Christopher A. Alabi. Effect of Composition on Antibacterial Activity of Sequence-Defined Cationic Oligothioetheramides. ACS Infectious Diseases 2018, 4 , 1257-1263. https://doi.org/10.1021/acsinfecdis.8b00079Youhong Niu, Minghui Wang, Yafei Cao, Alekhya Nimmagadda, Jianxing Hu, Yanfen Wu, Jianfeng Cai, Xin-Shan Ye. Rational Design of Dimeric Lysine N-Alkylamides as Potent and Broad-Spectrum Antibacterial Agents. Journal of Medicinal Chemistry 2018, 61 , 2865-2874. https://doi.org/10.1021/acs.jmedchem.7b01704Ma Su, Donglin Xia, Peng Teng, Alekhya Nimmagadda, Chao Zhang, Timothy Odom, Annie Cao, Yong Hu, and Jianfeng Cai . Membrane-Active Hydantoin Derivatives as Antibiotic Agents. Journal of Medicinal Chemistry 2017, 60 (20) , 8456-8465. https://doi.org/10.1021/acs.jmedchem.7b00847Mintu Porel, Dana N. Thornlow, Christine M. Artim, and Christopher A. Alabi . Sequence-Defined Backbone Modifications Regulate Antibacterial Activity of OligoTEAs. ACS Chemical Biology 2017, 12 , 715-723. https://doi.org/10.1021/acschembio.6b00837Olapeju Bolarinwa, Alekhya Nimmagadda, Ma Su, and Jianfeng Cai . Structure and Function of AApeptides. Biochemistry 2017, 56 , 445-457. https://doi.org/10.1021/acs.biochem.6b01132Alekhya Nimmagadda, Xuan Liu, Peng Teng, Ma Su, Yaqiong Li, Qiao Qiao, Nawal K. Khadka, Xiaoting Sun, Jianjun Pan, Hai Xu, Qi Li, and Jianfeng Cai . Polycarbonates with Potent and Selective Antimicrobial Activity toward Gram-Positive Bacteria. Biomacromolecules 2017, 18 , 87-95. https://doi.org/10.1021/acs.biomac.6b01385Peng Teng, Da Huo, Alekhya Nimmagadda, Jianfeng Wu, Fengyu She, Ma Su, Xiaoyang Lin, Jiyu Yan, Annie Cao, Chuanwu Xi, Yong Hu, and Jianfeng Cai . Small Antimicrobial Agents Based on Acylated Reduced Amide Scaffold. Journal of Medicinal Chemistry 2016, 59 (17) , 7877-7887. https://doi.org/10.1021/acs.jmedchem.6b00640Fengyu She, Alekhya Nimmagadda, Peng Teng, Ma Su, Xiaobing Zuo, and Jianfeng Cai . Helical 1:1 α/Sulfono-γ-AA Heterogeneous Peptides with Antibacterial Activity. Biomacromolecules 2016, 17 , 1854-1859. https://doi.org/10.1021/acs.biomac.6b00286Yan Shi, Peng Teng, Peng Sang, Fengyu She, Lulu Wei, and Jianfeng Cai . γ-AApeptides: Design, Structure, and Applications. Accounts of Chemical Research 2016, 49 , 428-441. https://doi.org/10.1021/acs.accounts.5b00492Divakara S. S. M. Uppu and Jayanta Haldar . Lipopolysaccharide Neutralization by Cationic-Amphiphilic Polymers through Pseudoaggregate Formation. Biomacromolecules 2016, 17 , 862-873. https://doi.org/10.1021/acs.biomac.5b01567Yaqiong Li, Haifan Wu, Peng Teng, Ge Bai, Xiaoyang Lin, Xiaobing Zuo, Chuanhai Cao, and Jianfeng Cai . Helical Antimicrobial Sulfono-γ-AApeptides. Journal of Medicinal Chemistry 2015, 58 (11) , 4802-4811. https://doi.org/10.1021/acs.jmedchem.5b00537Alberto Oddo, Lena Münzker, and Paul R. Hansen . Peptide Macrocycles Featuring a Backbone Secondary Amine: A Convenient Strategy for the Synthesis of Lipidated Cyclic and Bicyclic Peptides on Solid Support. Organic Letters 2015, 17 (10) , 2502-2505. https://doi.org/10.1021/acs.orglett.5b01026Tsz Tin Yu, Rajesh Kuppusamy, Muhammad Yasir, Md. Musfizur Hassan, Manjulatha Sara, Junming Ho, Mark D. P. Willcox, David StC. Black, Naresh Kumar. Polyphenylglyoxamide-Based Amphiphilic Small Molecular Peptidomimetics as Antibacterial Agents with Anti-Biofilm Activity. International Journal of Molecular Sciences 2021, 22 (14) , 7344. https://doi.org/10.3390/ijms22147344Hidetomo Yokoo, Motoharu Hirano, Takashi Misawa, Yosuke Demizu. Helical Antimicrobial Peptide Foldamers Containing Non‐proteinogenic Amino Acids. ChemMedChem 2021, 16 , 1226-1233. https://doi.org/10.1002/cmdc.202000940Shreya Kanth, Akshatha Nagaraja, Yashoda Malgar Puttaiahgowda. Polymeric approach to combat drug-resistant methicillin-resistant Staphylococcus aureus. Journal of Materials Science 2021, 56 (12) , 7265-7285. https://doi.org/10.1007/s10853-021-05776-7Signe Kaustrup Jensen, Thomas T. Thomsen, Alberto Oddo, Henrik Franzyk, Anders Løbner-Olesen, Paul R. Hansen. Novel Cyclic Lipopeptide Antibiotics: Effects of Acyl Chain Length and Position. International Journal of Molecular Sciences 2020, 21 (16) , 5829. https://doi.org/10.3390/ijms21165829Minghui Wang, Ruixuan Gao, Peng Sang, Timothy Odom, Mengmeng Zheng, Yan Shi, Hai Xu, Chuanhai Cao, Jianfeng Cai. Dimeric γ-AApeptides With Potent and Selective Antibacterial Activity. Frontiers in Chemistry 2020, 8 https://doi.org/10.3389/fchem.2020.00441Mohini Mohan Konai, Swagatam Barman, Yash Acharya, Kathakali De, Jayanta Haldar. Recent development of antibacterial agents to combat drug-resistant Gram-positive bacteria. 2020,,, 71-104. https://doi.org/10.1016/B978-0-12-818480-6.00004-7Lulu Wei, Minghui Wang, Ruixuan Gao, Rojin Fatirkhorani, Jianfeng Cai. Antibacterial activity of lipo-α/sulfono-γ-AA hybrid peptides. European Journal of Medicinal Chemistry 2020, 186 , 111901. https://doi.org/10.1016/j.ejmech.2019.111901Yipeng Yuan, Yu Zai, Xinping Xi, Chengbang Ma, Lei Wang, Mei Zhou, Chris Shaw, Tianbao Chen. A novel membrane-disruptive antimicrobial peptide from frog skin secretion against cystic fibrosis isolates and evaluation of anti-MRSA effect using Galleria mellonella model. Biochimica et Biophysica Acta (BBA) - General Subjects 2019, 1863 , 849-856. https://doi.org/10.1016/j.bbagen.2019.02.013Mussie Gide, Alekhya Nimmagadda, Ma Su, Minghui Wang, Peng Teng, Chunpu Li, Ruixuan Gao, Hai Xu, Qi Li, Jianfeng Cai. Nano‐Sized Lipidated Dendrimers as Potent and Broad‐Spectrum Antibacterial Agents. Macromolecular Rapid Communications 2018, 39 (24) , 1800622. https://doi.org/10.1002/marc.201800622Emily A. Hoff, Christine M. Artim, Joseph S. Brown, Christopher A. Alabi. Sensitivity of Antibacterial Activity to Backbone Sequence in Constitutionally Isomeric OligoTEAs. Macromolecular Bioscience 2018, 18 (11) , 1800241. https://doi.org/10.1002/mabi.201800241Mojtaba Bagheri, Mehriar Amininasab, Margitta Dathe. Arginine/Tryptophan‐Rich Cyclic α/β‐Antimicrobial Peptides: The Roles of Hydrogen Bonding and Hydrophobic/Hydrophilic Solvent‐Accessible Surface Areas upon Activity and Membrane Selectivity. Chemistry – A European Journal 2018, 24 (53) , 14242-14253. https://doi.org/10.1002/chem.201802881Nurcan Karaman, Rabeah Adil Zainel, Handan A. Kapkaç, Hülya Karaca Gençer, Sinem Ilgın, A. Burak Karaduman, Ayşegül Karaküçük-İyidoğan, Emine E. Oruç-Emre, Bedia Koçyiğit-Kaymakçıoğlu. Design and evaluation of biological activities of 1,3-oxazolidinone derivatives bearing amide, sulfonamide, and thiourea moieties. Archiv der Pharmazie 2018, 351 , 1800057. https://doi.org/10.1002/ardp.201800057Olapeju Bolarinwa, Jianfeng Cai. Developments with investigating descriptors for antimicrobial AApeptides and their derivatives. Expert Opinion on Drug Discovery 2018, 13 , 727-739. https://doi.org/10.1080/17460441.2018.1487950Sylvia Singh, Alekhya Nimmagadda, Ma Su, Minghui Wang, Peng Teng, Jianfeng Cai. Lipidated α/α-AA heterogeneous peptides as antimicrobial agents. European Journal of Medicinal Chemistry 2018, 155 , 398-405. https://doi.org/10.1016/j.ejmech.2018.06.006Claira Arul Aruldass, Santhana Raj Louis Masalamany, Chidambaram Kulandaisamy Venil, Wan Azlina Ahmad. Antibacterial mode of action of violacein from Chromobacterium violaceum UTM5 against Staphylococcus aureus and methicillin-resistant Staphylococcus aureus (MRSA). Environmental Science and Pollution Research 2018, 25 , 5164-5180. https://doi.org/10.1007/s11356-017-8855-2Alicia Boto, Jose Pérez de la Lastra, Concepción González. The Road from Host-Defense Peptides to a New Generation of Antimicrobial Drugs. Molecules 2018, 23 , 311. https://doi.org/10.3390/molecules23020311Naiem Ahmad Wani, Gurpreet Singh, Sudha Shankar, Arushi Sharma, Meenu Katoch, Rajkishor Rai. Short hybrid peptides incorporating β- and γ-amino acids as antimicrobial agents. Peptides 2017, 97 , 46-53. https://doi.org/10.1016/j.peptides.2017.09.016Jun-Jie Koh, Shuimu Lin, Roger W. Beuerman, Shouping Liu. Recent advances in synthetic lipopeptides as anti-microbial agents: designs and synthetic approaches. Amino Acids 2017, 49 (10) , 1653-1677. https://doi.org/10.1007/s00726-017-2476-4Natalia Molchanova, Paul Hansen, Henrik Franzyk. Advances in Development of Antimicrobial Peptidomimetics as Potential Drugs. Molecules 2017, 22 , 1430. https://doi.org/10.3390/molecules22091430Hülya Karaca Gençer, Ulviye Acar Çevik, Serkan Levent, Begüm Sağlık, Büşra Korkut, Yusuf Özkay, Sinem Ilgın, Yusuf Öztürk. New Benzimidazole-1,2,4-Triazole Hybrid Compounds: Synthesis, Anticandidal Activity and Cytotoxicity Evaluation. Molecules 2017, 22 , 507. https://doi.org/10.3390/molecules22040507Sarah Line Skovbakke, Henrik Franzyk. Anti-inflammatory Properties of Antimicrobial Peptides and Peptidomimetics: LPS and LTA Neutralization. 2017,,, 369-386. https://doi.org/10.1007/978-1-4939-6737-7_27O. Oyesiku, J. Cai. Peptidomimetic Agents Targeting Bacteria. 2017,,, 179-193. https://doi.org/10.1016/B978-0-12-409547-2.12564-8Fengyu She, Olapeju Oyesiku, Peiguang Zhou, Shiming Zhuang, David W Koenig, Jianfeng Cai. The development of antimicrobial γ-AApeptides. Future Medicinal Chemistry 2016, 8 (10) , 1101-1110. https://doi.org/10.4155/fmc-2016-0034Peng Teng, Yan Shi, Peng Sang, Jianfeng Cai. γ‐AApeptides as a New Class of Peptidomimetics. Chemistry – A European Journal 2016, 22 (16) , 5458-5466. https://doi.org/10.1002/chem.201504936Alberto Oddo, Nils T. Nyberg, Niels Frimodt-Møller, Peter W. Thulstrup, Paul R. Hansen. The effect of glycine replacement with flexible ω-amino acids on the antimicrobial and haemolytic activity of an amphipathic cyclic heptapeptide. European Journal of Medicinal Chemistry 2015, 102 , 574-581. https://doi.org/10.1016/j.ejmech.2015.08.028Biljana Mojsoska, Håvard Jenssen. Peptides and Peptidomimetics for Antimicrobial Drug Design. Pharmaceuticals 2015, 8 , 366-415. https://doi.org/10.3390/ph8030366Shruti Padhee, Yaqiong Li, Jianfeng Cai. Activity of lipo-cyclic γ-AApeptides against biofilms of Staphylococcus epidermidis and Pseudomonas aeruginosa. Bioorganic Medicinal Chemistry Letters 2015, 25 (12) , 2565-2569. https://doi.org/10.1016/j.bmcl.2015.04.039Peter T. Smith, Mia L. Huang, Kent Kirshenbaum. Osmoprotective polymer additives attenuate the membrane pore-forming activity of antimicrobial peptoids. Biopolymers 2015, 103 , 227-236. https://doi.org/10.1002/bip.22588Divakara S.S.M. Uppu, Chandradhish Ghosh, Jayanta Haldar. Surviving sepsis in the era of antibiotic resistance: Are there any alternative approaches to antibiotic therapy?. Microbial Pathogenesis 2015, 80 , 7-13. https://doi.org/10.1016/j.micpath.2015.02.001Haifan Wu, Qiao Qiao, Yaogang Hu, Peng Teng, Wenyang Gao, Xiaobing Zuo, Lukasz Wojtas, Randy W. Larsen, Shengqian Ma, Jianfeng Cai. Sulfono-γ-AApeptides as a New Class of Nonnatural Helical Foldamer. Chemistry - A European Journal 2015, 21 , 2501-2507. https://doi.org/10.1002/chem.201406112Peng Teng, Haifan Wu, Lili Lin, Jianfeng Cai. Antimicrobial γ-AApeptides (WO2013112548): a patent evaluation. Expert Opinion on Therapeutic Patents 2015, 25 , 111-118. https://doi.org/10.1517/13543776.2014.973855Haifan Wu, Fengyu She, Wenyang Gao, Austin Prince, Yaqiong Li, Lulu Wei, Allison Mercer, Lukasz Wojtas, Shengqian Ma, Jianfeng Cai. The synthesis of head-to-tail cyclic sulfono-γ-AApeptides. Organic Biomolecular Chemistry 2015, 13 , 672-676. https://doi.org/10.1039/C4OB02232GYaogang Hu , Ni Cheng , Haifan Wu, Samuel Kang, Richard D. Ye , Jianfeng Cai. Design, Synthesis and Characterization of fMLF-Mimicking AApeptides. ChemBioChem 2014, 15 (16) , 2420-2426. https://doi.org/10.1002/cbic.201402396Yaqiong Li, Christina Smith, Haifan Wu, Peng Teng, Yan Shi, Shruti Padhee, Torey Jones, Anh-My Nguyen, Chuanhai Cao, Hang Yin, Jianfeng Cai. Short Antimicrobial Lipo-α/γ-AA Hybrid Peptides. ChemBioChem 2014, 15 (15) , 2275-2280. https://doi.org/10.1002/cbic.201402264Shruti Padhee, Christina Smith, Haifan Wu, Yaqiong Li, Namitha Manoj, Qiao Qiao, Zoya Khan, Chuanhai Cao, Hang Yin, Jianfeng Cai. The Development of Antimicrobial α-AApeptides that Suppress Proinflammatory Immune Responses. ChemBioChem 2014, 15 , 688-694. https://doi.org/10.1002/cbic.201300709Peng Teng, Xiaolei Zhang, Haifan Wu, Qiao Qiao, Said M. Sebti, Jianfeng Cai. Identification of novel inhibitors that disrupt STAT3–DNA interaction from a γ-AApeptide OBOC combinatorial library. Chem. Commun. 2014, 50 (63) , 8739-8742. https://doi.org/10.1039/C4CC03909BExport articles to MendeleyGet article recommendations from ACS based on references in your Mendeley library.Export articles to MendeleyGet article recommendations from ACS based on references in your Mendeley library. Please note: If you switch to a different device, you may be asked to login again with only your ACS ID. Please note: If you switch to a different device, you may be asked to login again with only your ACS ID. Please note: If you switch to a different device, you may be asked to login again with only your ACS ID. Please login with your ACS ID before connecting to your Mendeley account.Login with ACS ID This website uses cookies to improve your user experience. By continuing to use the site, you are accepting our use of cookies. Read the ACS privacy policy. CONTINUE