We present on the first chemical synthesis of ultra-short pyrazole-arginine based antimicrobial peptidomimetics derived from the newly synthesized N-alkyl/aryl-pyrazole amino acids. Through systematic tuning of hydrophobicity, charge, and peptide length, we can obtain the shortest peptide Py11 with the most potent antimicrobial activity. Py11 displayed greater antimicrobial activity against antibiotic-resistant bacteria, including MRSA, MDRPA and VREF and was approximately 2-4 times higher than that of melittin. Besides its higher selectivity (therapeutic index) toward bacterial cells than LL-37, Py11 showed highly increased proteolytic stability against trypsin digestion, and maintained its antimicrobial activity in the presence of physiological salts. Interestingly, Py11 exhibited higher anti-biofilm activity against MDRPA compared to LL-37. The results from fluorescence spectroscopy, and transmission electron microscopy (TEM) suggested that Py11 kills bacterial cells possibly by integrity disruption damaging the cell membrane, leading to the cytosol leakage and eventual cell lysis. Furthermore, Py11 displayed significant anti-inflammatory (endotoxin-neutralizing) activity by inhibiting LPS-induced production of nitric oxide (NO) and TNF-alpha. Collectively, our results suggest that Py11 can serve a new class of antimicrobial and antisepsis agents.
Audience take away:
Synthesis of Fmoc-pyrazole amino acids for the first time
Ultra short peptidomimetics showed broad-spectrum of antimicrobial activity including MRSA, VREF, and MDRPA
Ultra short peptidomimetics also showed potent anti-biofilm activity.