Spermine-Conjugated Short Proline-Rich Lipopeptides as Broad-Spectrum Intracellular Targeting Antibacterial Agents

Rikeshwer Prasad Dewangan, Devesh Pratap Verma, Neeraj Kumar Verma, Ankit Gupta, Garima Pant, Kalyan Mitra, Saman Habib, Jimut Kanti Ghosh

Research output: Contribution to journalArticlepeer-review

12 Scopus citations


Toward the design of new proline-rich peptidomimetics, a short peptide segment, present in several proline-rich antimicrobial peptides (AMPs), was selected. Fatty acids of varying lengths and spermine were conjugated at the N- and C-terminals of the peptide, respectively. Spermine-conjugated lipopeptides, C10-PR-Spn and C12-PR-Spn, exhibited minimum inhibitory concentrations within 1.5-6.2 μM against the tested pathogens including resistant bacteria and insignificant hemolytic activity against human red blood cells up to 100 μM concentrations and demonstrated resistance against trypsin digestion. C10-PR-Spn and C12-PR-Spn showed synergistic antimicrobial activity against multidrug-resistant methicillin-resistant Staphylococcus aureus with several tested antibiotics. These lipopeptides did not permeabilize bacterial membrane-mimetic lipid vesicles or damage the Escherichia coli membrane like the nonmembrane-lytic AMP, buforin-II. The results suggested that C10-PR-Spn and C12-PR-Spn could interact with the 70S ribosome of E. coli and inhibit its protein synthesis. C10-PR-Spn and C12-PR-Spn demonstrated superior clearance of bacteria from the spleen, liver, and kidneys of mice, infected with S. aureus ATCC 25923 compared to levofloxacin.

Original languageEnglish
Pages (from-to)5433-5448
Number of pages16
JournalJournal of Medicinal Chemistry
Issue number7
StatePublished - 14 Apr 2022
Externally publishedYes

ASJC Scopus subject areas

  • Drug Discovery
  • Molecular Medicine


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