title: N-terminally modified linear and branched spermine backbone dipeptidomimetics against planktonic and sessile methicillin-resistant Staphylococcus aureus.
abstract: Toward the discovery of useful therapeutic molecules, we report the design and synthesis of a focused library of new ultrashort N-terminally modified dipeptidomimetics, with or without modifications in the spermine backbone leading to linear (series 1) or branched (series 2) tryptophans, as antimicrobial agents. Eight peptidomimetics in the library showed good antibacterial activity (MICs of 1.77 to 14.2 μg/ml) against methicillin-resistant Staphylococcus aureus (MRSA) and methicillin-resistant Staphylococcus epidermidis bacterial strains. Tryptophan fluorescence measurements on artificial bacterial or mammalian mimic membranes and assessment of the MRSA potential depolarization ability of the designed compounds revealed membrane interactions dependent on tryptophan positioning and N-terminal tagging. Among active peptidomimetics, compounds 1c and 1d were found to be nonhemolytic, displaying rapid bactericidal activity (at 4× MIC) against exponentially growing MRSA. Further, scanning electron microscopy of peptidomimetic 1c- and 1d-treated MRSA showed morphological changes with damage to cell walls, defining a membrane-active mode of action. Moreover, peptidomimetics 1c and 1d did not induce significant drug resistance in MRSA even after 17 passages. We also investigated the activity of these molecules against MRSA biofilms. At sub-MIC levels (∼2 to 4 μg/ml), both peptidomimetics inhibited biofilm formation. At concentrations higher than the MIC (35 to 140 μg/ml), peptidomimetics 1c and 1d significantly reduced the metabolic activity and biomass of mature (24-h) MRSA biofilms. These results were corroborated by confocal laser scanning microscopy (live/dead assay). The in vitro protease stability and lower cytotoxicity of peptidomimetics against peripheral blood mononuclear cells (PBMCs) support them being novel staphylocidal peptidomimetics. In conclusion, this study provides two peptidomimetics as potential leads for treatment of staphylococcal infections under planktonic and sessile conditions.
authors: Peptide Research Laboratory, CSIR-Institute of Genomics and Integrative Biology, Delhi, India Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Jamia Hamdard, New Delhi, India.
authors: Rikeshwer Prasad
authors: RP
authors: Dewangan
authors: Peptide Research Laboratory, CSIR-Institute of Genomics and Integrative Biology, Delhi, India.
authors: Seema
authors: S
authors: Joshi
authors: Peptide Research Laboratory, CSIR-Institute of Genomics and Integrative Biology, Delhi, India.
authors: Shalini
authors: S
authors: Kumari
authors: Systems Biology Group, CSIR-Institute of Genomics and Integrative Biology, Delhi, India.
authors: Hemlata
authors: H
authors: Gautam
authors: Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Jamia Hamdard, New Delhi, India.
authors: Mohammed Shahar
authors: MS
authors: Yar
authors: Peptide Research Laboratory, CSIR-Institute of Genomics and Integrative Biology, Delhi, India spasha@igib.res.in.
authors: Santosh
authors: S
authors: Pasha
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology; D018441:Biofilms / Q000187:drug effects; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000382:microbiology; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects*; D008826:Microbial Sensitivity Tests / Q000379:methods; D010933:Plankton / Q000187:drug effects*; D013096:Spermine / Q000737:chemistry* / Q000494:pharmacology*; D013203:Staphylococcal Infections / Q000188:drug therapy*; D013212:Staphylococcus epidermidis / Q000187:drug effects
chemical_list: D000900:Anti-Bacterial Agents; D013096:Spermine