TY - JOUR
T1 - Spermine-Conjugated Short Proline-Rich Lipopeptides as Broad-Spectrum Intracellular Targeting Antibacterial Agents
AU - Dewangan, Rikeshwer Prasad
AU - Verma, Devesh Pratap
AU - Verma, Neeraj Kumar
AU - Gupta, Ankit
AU - Pant, Garima
AU - Mitra, Kalyan
AU - Habib, Saman
AU - Ghosh, Jimut Kanti
N1 - Funding Information:
This work was financially supported by the CSIR-CDRI and SERB-DST. R.P.D. is thankful to the Science Engineering Research Board (SERB) for the National Postdoctoral fellowship (NPDF, file no. PDF/2016/001872), and D.P.V. is thankful to the UGC for the Senior Research Fellowship.
Publisher Copyright:
© 2022 American Chemical Society. All rights reserved.
PY - 2022/4/14
Y1 - 2022/4/14
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85127308381&partnerID=8YFLogxK
U2 - 10.1021/acs.jmedchem.1c01809
DO - 10.1021/acs.jmedchem.1c01809
M3 - Article
C2 - 35297625
AN - SCOPUS:85127308381
SN - 0022-2623
VL - 65
SP - 5433
EP - 5448
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 7
ER -