2. Academic Validation
  3. Small Amphiphilic Peptides: Activity Against a Broad Range of Drug-Resistant Bacteria and Structural Insight into Membranolytic Properties

Small Amphiphilic Peptides: Activity Against a Broad Range of Drug-Resistant Bacteria and Structural Insight into Membranolytic Properties

  • J Med Chem. 2022 Jan 13;65(1):665-687. doi: 10.1021/acs.jmedchem.1c01782.
Sandeep Lohan 1 2,  Dindyal Mandal 1 2 3,  Wonsuk Choi 4,  Anastasia G Konshina 5,  Rakesh K Tiwari 1,  Roman G Efremov 5 6 7,  Innokentiy Maslennikov 4,  Keykavous Parang 1
Affiliations

Affiliations

  • 1 Center for Targeted Drug Delivery, Department of Biomedical and Pharmaceutical Sciences, Chapman University School of Pharmacy, Harry and Diane Rinker Health Science Campus, 9401 Jeronimo Road, Irvine, California 92618, United States.
  • 2 AJK Biopharmaceutical, 5270 California Avenue, Irvine, California 92617, United States.
  • 3 School of Biotechnology, KIIT Deemed to be University, Bhubaneswar 751024, India.
  • 4 Structural Biology Research Center, Department of Biomedical and Pharmaceutical Sciences, Chapman University School of Pharmacy, Harry and Diane Rinker Health Science Campus, 9401 Jeronimo Road, Irvine, California 92618, United States.
  • 5 M.M. Shemyakin & Yu.A. Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Miklukho-Maklaya Street, 16/10, Moscow 117997, Russia.
  • 6 National Research University Higher School of Economics, Myasnitskaya ul. 20, Moscow 101000, Russia.
  • 7 Moscow Institute of Physics and Technology (State University), Dolgoprudny, 141701 Moscow, Oblast, Russia.
PMID: 34978443 DOI: 10.1021/acs.jmedchem.1c01782
Abstract

We report the synthesis and Antibacterial activities of a series of amphiphilic membrane-active Peptides composed, in part, of various nongenetically coded hydrophobic Amino acids. The lead cyclic Peptides, 8C and 9C, showed broad-spectrum activity against drug-resistant Gram-positive (minimum inhibitory concentration (MIC) = 1.5-6.2 μg/mL) and Gram-negative (MIC = 12.5-25 μg/mL) bacteria. The cytotoxicity study showed the predominant lethal action of the Peptides against bacteria as compared with mammalian cells. A plasma stability study revealed approximately 2-fold higher stability of lead cyclic Peptides as compared to their linear counterparts after 24 h of incubation. A calcein dye leakage experiment revealed the membranolytic effect of the cyclic Peptides. Nuclear magnetic resonance spectroscopy and molecular dynamics simulation studies of the interaction of the Peptides with the phospholipid bilayer provided a solid structural basis to explain the membranolytic action of the Peptides with atomistic details. These results highlight the potential of newly designed amphiphilic Peptides as the next generation of peptide-based Antibiotics.

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