ACS Publications. Most Trusted. Most Cited. Most Read
My Activity

Figure 1Loading Img

Discovery of Peptide Antibiotics Composed of d-Amino Acids

  • Emel Adaligil
    Emel Adaligil
    Department of Chemistry, Tufts University, Medford, Massachusetts 02155, United States
  • Kalyani Patil
    Kalyani Patil
    Department of Chemistry, Tufts University, Medford, Massachusetts 02155, United States
  • Marissa Rodenstein
    Marissa Rodenstein
    Department of Chemistry, Tufts University, Medford, Massachusetts 02155, United States
  • , and 
  • Krishna Kumar*
    Krishna Kumar
    Department of Chemistry, Tufts University, Medford, Massachusetts 02155, United States
    Department of Biomedical Engineering, Tufts University, Medford, Massachusetts 02155, United States
    Cancer Center, Tufts Medical Center, Boston, Massachusetts 02110, United States
    *E-mail: [email protected]
Cite this: ACS Chem. Biol. 2019, 14, 7, 1498–1506
Publication Date (Web):June 3, 2019
Copyright © 2019 American Chemical Society

    Article Views





    Other access options
    Supporting Info (1)»


    Abstract Image

    A paucity of viable programs and pipelines for the discovery of new antibiotics poses a significant public health threat. The emergence of resistant strains against vancomycin is particularly dangerous in hospital settings. Here, we report the design of enantiomeric targets based on bacterial cell wall biosynthesis precursors that allow for selection and identification of short linear, cyclic and bicyclic peptides that are composed of d-amino acids. These compounds are active against Staphylococcus aureus, Methicillin-resistant S. aureus, and vancomycin-resistant Enterococci that possess moderately high antibacterial activity and furthermore display no toxicity to both human red blood cells and mammalian cells at these concentrations. This ‘mirror image phage display’ approach yielded templates that can serve as scaffolds for further improvements in activity-based structural modifications. This strategy has the potential to provide a new class of antimicrobials that are metabolically stable and have the promise for oral delivery. The use of this platform combined with traditional medicinal chemistry approaches could rapidly yield large numbers of new therapeutic lead compounds.

    Read this article

    To access this article, please review the available access options below.

    Get instant access

    Purchase Access

    Read this article for 48 hours. Check out below using your ACS ID or as a guest.


    Access through Your Institution

    You may have access to this article through your institution.

    Your institution does not have access to this content. You can change your affiliated institution below.

    Supporting Information

    Jump To

    The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acschembio.9b00234.

    • Experimental procedures of the synthesis and spectroscopic data for target molecules (Cep-1, Ala-2, Ala-3, and Ala-4), phage display screening protocols, chemical synthesis of peptides, antibacterial activity assays, cytotoxicity assays, protease stability assays, hemolytic activity, and accumulation of bacterial cell wall assays. Figures S1–S21 and Tables S1–S4 (PDF)

    Terms & Conditions

    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:

    Cited By

    This article is cited by 24 publications.

    1. Morgan E. Schafer, Hailee Browne, Joanna B. Goldberg, David E. Greenberg. Peptides and Antibiotic Therapy: Advances in Design and Delivery. Accounts of Chemical Research 2021, 54 (10) , 2377-2385.
    2. Michael Kelly, Samantha Cambray, Kelly A. McCarthy, Wenjian Wang, Edward Geisinger, Juan Ortiz-Marquez, Tim van Opijnen, Jianmin Gao. Peptide Probes of Colistin Resistance Discovered via Chemically Enhanced Phage Display. ACS Infectious Diseases 2020, 6 (9) , 2410-2418.
    3. Avinash Y. Gahane, Devesh Pratap Verma, Swagata Sarkar, Ashwani K. Thakur. Evaluation of Pharmacokinetic and Pharmacodynamic (PK/PD) of Novel Fluorenylmethoxycarbonyl- Phenylalanine Antimicrobial Agent. Pharmaceutical Research 2024, 41 (4) , 687-698.
    4. Eun‐Sol Choi, Hee‐Chan Jeong, Ye‐Lin Han, Hyo‐Jun Lee, Keiji Maruoka. Efficient Amide Formation from Non‐Activated Cyclopropyl Ester via Acyl Fluoride Generation Using Hypervalent Iodine(III) Reagent and Selectfluor. Asian Journal of Organic Chemistry 2023, 12 (9)
    5. John Fetse, Sashi Kandel, Umar-Farouk Mamani, Kun Cheng. Recent advances in the development of therapeutic peptides. Trends in Pharmacological Sciences 2023, 44 (7) , 425-441.
    6. Katriona Harrison, Angus S. Mackay, Lucas Kambanis, Joshua W. C. Maxwell, Richard J. Payne. Synthesis and applications of mirror-image proteins. Nature Reviews Chemistry 2023, 7 (6) , 383-404.
    7. Haoran Zhang, Panjing Lv, Jingrui Jiang, Yahui Liu, Ruixi Yan, Sainan Shu, Bing Hu, Han Xiao, Kun Cai, Shuai Yuan, Yan Li. Advances in developing ACE2 derivatives against SARS-CoV-2. The Lancet Microbe 2023, 4 (5) , e369-e378.
    8. Peng Zheng, Rongyu Li, Fangkai Li, Ruonan Wang, Senhe Qian. Exploration of Biological Properties and Antibacterial Action against Escherichia coli and Staphylococcus aureus of (LLKK) 3 ‐Derived Peptides. ChemistrySelect 2023, 8 (12)
    9. Hui Zhao, Dan Nie, Yue Hu, Zhou Chen, Zheng Hou, Mingkai Li, Xiaoyan Xue. Phage Display-Derived Peptides and Antibodies for Bacterial Infectious Diseases Therapy and Diagnosis. Molecules 2023, 28 (6) , 2621.
    10. Zijian Wang, Weikang Hu, Wang Wang, Yu Xiao, Yun Chen, Xinghuan Wang. Antibacterial Electrospun Nanofibrous Materials for Wound Healing. Advanced Fiber Materials 2023, 5 (1) , 107-129.
    11. Hyo‐Jun Lee, Eun‐Sol Choi, Keiji Maruoka. Development of a Catalytic Ester Activation Protocol for the Efficient Formation of Amide Bonds using an Ar−I/HF⋅pyridine/ m CPBA System. Asian Journal of Organic Chemistry 2022, 11 (10)
    12. Yong‐Kang Mei, Xiang‐Ting Min, Shi‐Yu Guo, Chang‐Hui Liu, Xiang‐Xin Zhang, Ding‐Wei Ji, Boshun Wan, Qing‐An Chen. Photo‐Induced Construction of N ‐Aryl Amides by Fe Catalysis. European Journal of Organic Chemistry 2022, 2022 (14)
    13. Prakash Kishore Hazam, Chimanjita Phukan, R. Akhil, Anjali Singh, Vibin Ramakrishnan. Antimicrobial effects of syndiotactic polypeptides. Scientific Reports 2021, 11 (1)
    14. Yosuke Sumida, Masayuki Yamasaki, Yoshiaki Nishiya, Shinya Kumagai, Toshihide Yamada, Masayuki Azuma. Protein Engineering of d ‐Succinylase from Cupriavidus sp . for d ‐Amino Acid Synthesis and the Structural Implications. Advanced Synthesis & Catalysis 2021, 363 (20) , 4770-4778.
    15. I. B. Nikitina, I. V. Goretova, I. V. Fedoseev. Through the Looking Glass of Biotechnology: D-Proteins as Objects of Patent Protection. Russian Journal of Bioorganic Chemistry 2021, 47 (5) , 1014-1019.
    16. Wataru Muramatsu, Tomohiro Hattori, Hisashi Yamamoto. Amide bond formation: beyond the dilemma between activation and racemisation. Chemical Communications 2021, 57 (52) , 6346-6359.
    17. Jie Zhu, Yibing Huang, Cuihua Hu, Yuxi Huang, Mingxia Chen, Xu He, Yanan Zhang, Yiou Wang, Yuxin Chen. Inhibitory Effects and Mechanism of the Combined Use of α-Helical Peptides HPRP-A1/HPRP-A2 and Chlorhexidine Acetate Against Bacterial and Fungal Biofilms. International Journal of Peptide Research and Therapeutics 2021, 27 (1) , 527-542.
    18. Han-Ying Zhu, Meng Wu, Fei-Qiang Yu, Yan-Ni Zhang, Tong-Kuai Xi, Kai Chen, Ge-Min Fang. Chemical synthesis of thioether-bonded bicyclic peptides using tert-butylthio and Trt-protected cysteines. Tetrahedron Letters 2021, 67 , 152875.
    19. Olga V. Makhlynets, Gregory A. Caputo. Characteristics and therapeutic applications of antimicrobial peptides. Biophysics Reviews 2021, 2 (1)
    20. Hyo-Jun Lee, Xiao Huang, Shigeyoshi Sakaki, Keiji Maruoka. Metal-free approach for hindered amide-bond formation with hypervalent iodine( iii ) reagents: application to hindered peptide synthesis. Green Chemistry 2021, 23 (2) , 848-855.
    21. Krištof Bozovičar, Tomaž Bratkovič. Small and Simple, yet Sturdy: Conformationally Constrained Peptides with Remarkable Properties. International Journal of Molecular Sciences 2021, 22 (4) , 1611.
    22. Alessandra Murabito, Sophie Cnudde, Emilio Hirsch, Alessandra Ghigo. Potential therapeutic applications of AKAP disrupting peptides. Clinical Science 2020, 134 (24) , 3259-3282.
    23. Ying Li, Xiuxiu Cao, Changlin Tian, Ji-Shen Zheng. Chemical protein synthesis-assisted high-throughput screening strategies for d-peptides in drug discovery. Chinese Chemical Letters 2020, 31 (9) , 2365-2374.
    24. Cíntia A. P. da Costa, Gabriel S. Vignoli Muniz, Philippe Boduch, Hermann Rothard, Enio F. da Silveira. Valine Radiolysis by H+, He+, N+, and S15+ MeV Ions. International Journal of Molecular Sciences 2020, 21 (5) , 1893.

    Pair your accounts.

    Export articles to Mendeley

    Get article recommendations from ACS based on references in your Mendeley library.

    Pair your accounts.

    Export articles to Mendeley

    Get article recommendations from ACS based on references in your Mendeley library.

    You’ve supercharged your research process with ACS and Mendeley!

    STEP 1:
    Click to create an 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 note: If you switch to a different device, you may be asked to login again with only your ACS ID.

    Your Mendeley pairing has expired. Please reconnect