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Roles of the Conserved Amino Acid Residues in Reduced Human Defensin 5: Cysteine and Arginine Are Indispensable for Its Antibacterial Action and LPS Neutralization
Author(s) -
Chen Fang,
Tang Yong,
Zheng Hong,
Xu Yang,
Wang Junping,
Wang Cheng
Publication year - 2019
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201900282
Subject(s) - peptide , chemistry , biochemistry , lipopolysaccharide , defensin , cysteine , arginine , amino acid , antimicrobial peptides , antibiotics , biology , enzyme , endocrinology
Antimicrobial peptides (AMPs) that are able to neutralize toxins are promising antibiotics. In this study we investigated the role of structurally conserved amino acids in reduced human defensin 5 (HD5 RED ), which is an endogenous peptide with antibacterial action and the ability to neutralize lipopolysaccharide (LPS). Cys residues and high Arg content, rather than Gly 18 and Arg 6 –Glu 14 , were found to be indispensable for HD5 RED binding to lipid A, for penetrating the bacterial outer and inner membranes, and for eliminating bacteria. Otherwise, all the conserved sites were requisite for HD5 RED to block the interaction between LPS and LPS‐binding protein and to suppress the TLR4–NF‐κB signaling pathway initiated by LPS. Accordingly, we designed the acetamidomethylated Acm Cys‐E21R‐HD5 RED , which was much more potent than HD5 RED at eliminating bacteria and which can neutralize LPS. Acm Cys‐E21R‐HD5 RED was also found to exhibit a synergistic effect with ciprofloxacin in killing multidrug‐resistant Acinetobacter baumannii . The results of this study, in which multifunctional AMPs were designed based on structure–activity research, may help in the development of more peptide antibiotics.