Tandem Repeat of a Short Human Chemerin-Derived Peptide and Its Nontoxic <scp>d</scp>-Lysine-Containing Enantiomer Display Broad-Spectrum Antimicrobial and Antitubercular Activities
Devesh Pratap Verma, Mohd Mustkim Ansari, Neeraj Kumar Verma, Jyotshana Saroj, Sariyah Akhtar, Garima Pant, Kalyan Mitra, B. N. Singh, Jimut Kanti Ghosh
Abstract
To design novel antimicrobial peptides by utilizing the sequence of the human host defense protein, chemerin, a seven-residue amphipathic stretch located in the amino acid region, 109–115, was identified, which possesses the highest density of hydrophobic and positively charged residues. Although this 7-mer peptide was inactive toward microorganisms, its 14-mer tandem repeat (Chem-KVL) was highly active against different bacteria including methicillin-resistant Staphylococcus aureus, a multidrug-resistant Staphylococcus aureus strain, and slow- and fast-growing mycobacterial species. The selective enantiomeric substitutions of its two l-lysine residues were attempted to confer cell selectivity and proteolytic stability to Chem-KVL. Chem-8dK with a d-lysine replacement in its middle (eighth position) showed the lowest hemolytic activity against human red blood cells among Chem-KVL analogues and maintained high antimicrobial properties. Chem-8dK showed in vivo efficacy against Pseudomonas aeruginosa infection in BALB/c mice and inhibited the development of resistance in this microorganism up to 30 serial passages and growth of intracellular mycobacteria in THP-1 cells.