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

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.