Journal
AMINO ACIDS
Volume 46, Issue 1, Pages 187-198Publisher
SPRINGER WIEN
DOI: 10.1007/s00726-013-1616-8
Keywords
SMAP-18; Trp-substituted SMAP-18 analog; Cell selectivity; Mammalian cell toxicity; Bacterial killing mechanism
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To develop short antimicrobial peptide with improved cell selectivity and reduced mammalian cell toxicity compared to sheep myeloid antimicrobial peptide-29 (SMAP-29) and elucidate the possible mechanisms responsible for their antimicrobial action, we synthesized a N-terminal 18-residue peptide amide (SMAP-18) from SMAP-29 and its Trp-substituted analog (SMAP-18-W). Due to their reduced hemolytic activity and retained antimicrobial activity, SMAP-18 and SMAP-18-W showed higher cell selectivity than SMAP-29. In addition, SMAP-18 and SMAP-18-W had no cytotoxicity against three different mammalian cells such as RAW 264.7, NIH-3T3 and HeLa cells even at 100 mu M. These results suggest that SMAP-18 and SMAP-18-W have potential for future development as novel therapeutic antimicrobial agent. Unlike SMAP-29, SMAP-18 and SMAP-18-W showed relatively weak ability to induce dye leakage from bacterial membrane-mimicking liposomes, N-phenyl-1-napthylamine (NPN) uptake and o-nitrophenyl-beta-galactoside (ONPG) hydrolysis. Similar to SMAP-29, SMAP-18-W led to a significant membrane depolarization (> 80 %) against Staphylococcus aureus at 2 x MIC. In contrast, SMAP-18 did not cause any membrane depolarization even at 4 x MIC. In confocal laser scanning microscopy, we observed translocation of SMAP-18 across the membrane in a non-membrane disruptive manner. SMAP-29 and SMAP-18-W were unable to translocate the bacterial membrane. Collectively, we propose here that SMAP-29 and SMAP-18-W kill microorganisms by disrupting/perturbing the lipid bilayer and forming pore/ion channels on bacterial cell membranes, respectively. In contrast, SMAP-18 may kill bacteria via intracellular-targeting mechanism.
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