Adding a C-terminal Cysteine (CTC) Can Enhance the Bactericidal Activity of Three Different Antimicrobial Peptides

Abstract

The emergence of antibiotic-resistant bacteria has threatened our health worldwide. There is an urgent need for novel antibiotics. Previously, we identified a novel 37-mer antimicrobial peptide (AMP), HBcARD, with broad spectrum antimicrobial activity. Here, we improved the efficacy of HBcARD, by re-engineering the peptide, including the addition of a new cysteine to its C-terminus (CTC). The new 28-mer derivative, D-150-177C, contains all D-form arginines, in addition to a C-terminal cycteine. This peptide can kill antibiotic-resistant clinical isolates of Gram-negative bacteria, and is more potent than the parental HBcARD peptide in a mouse sepsis model. In another lung infection mouse model, D-150-177C showed protection efficacy against colistin-resistant Acinetobacter baumannii. Unlike colistin, we observed no acute toxicity of D-150-177C in vivo. Interestingly, we found that CTC modification could enhance the antibacterial activity of several other AMPs, such as buforinII and lysin. The potential application and mechanism of this CTC method as a general approach to improving drug efficacy, warrants further investigation in the future.

Structural stability of antimicrobial peptides rich in tryptophan, proline and arginine: a computational study

“…Antimicrobial peptides have a high presence of some specific amino acids such as cysteine (Chen et al, 2018), glycine (Dong et al, 2017;Ili c et al, 2013;Verdon et al, 2016), histidine (Dong et al, 2017), proline (Mishra et al, 2018), tryptophan (Chan et al, 2006;Dong et al, 2012). Among these different types of antimicrobial peptides, proline-rich antimicrobial peptides and tryptophan-rich antimicrobial peptides have involved particular interest due to their broad distribution among various organisms, in addition to antimicrobial peptides can target various intracellular targets.…”

“…Arginine residues enhance cationic charges and hydrogen bonding properties to peptides, which are essential for interaction with bacterial membranes (Chan et al, 2006). In some cases, modifying AMPs with D-form amino acids and chimeric AMPs had shown to enhance stability and bactericidal potency (Chen et al, 2018).…”

Prevalence and sequence of aminoglycosides modifying enzymes genes among E.coli and Klebsiella species isolated from Egyptian hospitals

“…The emergence of antibiotics resistance bacteria has threaten our health worldwide. This has triggered initiatives worldwide to develop novel and more effective antimicrobial compounds and develop novel delivery and targeting strategies (Baptista et al, 2018;Chen, Su, Kuo, Lauderdale, & Shih, 2018). Antimicrobial resistance has become a serious global health concern causing complication in treatment strategies, consequently increasing the cost of health care (Mohammed, Gadzama, Zailani, & Aboderin, 2016).…”

Addition of L-cysteine to the N- or C-terminus of the all-D-enantiomer [D(KLAKLAK)2] increases antimicrobial activities against multidrug-resistant Pseudomonas aeruginosa, Acinetobacter baumannii and Escherichia coli

“…This attachment yielded two compounds (DP-C and C-DP) with significantly greater antimicrobial activities against A. baumannii , E. coli and P. aeruginosa than the original DP. Similarly, the addition of L-cysteine to AMPs (Andersonin-Y1, HBcARD, buforinII or lysin) enhanced its antimicrobial activity, with higher membrane disruption activity than the original peptide ( Chen et al, 2018 ; Pal et al, 2019 ). The cysteine-derived cationic dipeptides lysine–cysteine, arginine–cysteine and histidine–cysteine presented antimicrobial activity, SEM analysis suggests that these dipeptides interact with cell walls to disrupt membrane integrity ( Tsai et al, 2020 ).…”

“…The cysteine-derived cationic dipeptides lysine–cysteine, arginine–cysteine and histidine–cysteine presented antimicrobial activity, SEM analysis suggests that these dipeptides interact with cell walls to disrupt membrane integrity ( Tsai et al, 2020 ). Whereas addition of an L-cysteine to the C-terminus of indolicidin, magainine or epinecidin-1 did not change their antimicrobial activity ( Chen et al, 2018 ). It remains unclear what could be the mechanism by which the addition of cysteine to the N- or C-terminus to AMPs enhances antimicrobial activity.…”