Truncated and constrained helical analogs of antimicrobial esculentin-2EM

Pham, Thanh K.; Kim, Do-Hee; Lee, Bong-Jin; Kim, Young Woo

doi:10.1016/j.bmcl.2013.10.031

Cited by 35 publications

(33 citation statements)

References 33 publications

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“…The chosen peptide contains 11 residues corresponding to the α2 helix region of HicA (KYTERGIRKQA) and 11 residues corresponding to the interface between HicA and HicB; these residues are underlined. Peptides mimicking the helix are preferred because of their resistance to proteolytic degradation ( 74 ). Due to its membrane affinity and selectivity, the modeled helix should not be divided.…”

Section: Resultsmentioning

confidence: 99%

Functional insights into the Streptococcus pneumoniae HicBA toxin–antitoxin system based on a structural study

Kim

Kang

Park

et al. 2018

Nucleic Acids Research

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Streptococcus pneumonia has attracted increasing attention due to its resistance to existing antibiotics. TA systems are essential for bacterial persistence under stressful conditions such as nutrient deprivation, antibiotic treatment, and immune system attacks. In particular, S. pneumoniae expresses the HicBA TA gene, which encodes the stable HicA toxin and the labile HicB antitoxin. These proteins interact to form a non-toxic TA complex under normal conditions, but the toxin is activated by release from the antitoxin in response to unfavorable growth conditions. Here, we present the first crystal structure showing the complete conformation of the HicBA complex from S. pneumonia. The structure reveals that the HicA toxin contains a double-stranded RNA-binding domain that is essential for RNA recognition and that the C-terminus of the HicB antitoxin folds into a ribbon-helix-helix DNA-binding motif. The active site of HicA is sterically blocked by the N-terminal region of HicB. RNase activity assays show that His36 is essential for the ribonuclease activity of HicA, and nuclear magnetic resonance (NMR) spectra show that several residues of HicB participate in binding to the promoter DNA of the HicBA operon. A toxin-mimicking peptide that inhibits TA complex formation and thereby increases toxin activity was designed, providing a novel approach to the development of new antibiotics.

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Section: Resultsmentioning

confidence: 99%

Functional insights into the Streptococcus pneumoniae HicBA toxin–antitoxin system based on a structural study

Kim

Kang

Park

et al. 2018

Nucleic Acids Research

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“…However, high synthesis cost and systemic toxicity have been challenges for the further application of natural peptides. Recently, modification of natural AMPs has been shown to be an effective strategy for reducing the manufacturing cost and limiting the toxicity15282930. In our previous study, we reported an α-helical peptide derived from the natural peptide PMAP-36 by deleting the unstructured C-terminus.…”

Section: Discussionmentioning

confidence: 99%

Antimicrobial activity, improved cell selectivity and mode of action of short PMAP-36-derived peptides against bacteria and Candida

Lyu

Yang

Lyu

et al. 2016

Sci Rep

178

148

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Antimicrobial peptides (AMPs) have recently attracted a great deal of attention as promising antibiotic candidates, but some obstacles such as toxicity and high synthesis cost must be addressed before developing them further. For developing short peptides with improved cell selectivity, we designed a series of modified PMAP-36 analogues. Antimicrobial assays showed that decreasing chain length in a certain range retained the high antimicrobial activity of the parental peptide and reduced hemolysis. The 18-mer peptide RI18 exhibited excellent antimicrobial activity against both bacteria and fungi, and its hemolytic activity was observably lower than PMAP-36 and melittin. The selectivity indexes of RI18 against bacteria and fungi were improved approximately 19-fold and 108-fold, respectively, compared to PMAP-36. In addition, serum did not affect the antibacterial activity of RI18 against E. coli but inhibited the antifungal efficiency against C. albicans. Flow cytometry and electron microscopy observation revealed that RI18 killed microbial cells primarily by damaging membrane integrity, leading to whole cell lysis. Taken together, these results suggest that RI18 has potential for further therapeutic research against frequently-encountered bacteria and fungi. Meanwhile, modification of AMPs is a promising strategy for developing novel antimicrobials to overcome drug-resistance.

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“…22 However, the intrinsic cell permeability of another SP called NYAD-1, 23 which inhibits the capsid assembly of HIV-1, was described as preferentially adopting parallel orientation to permeate through the lipid bilayers even at low-solution concentrations. 26 Both studies demonstrated that stapling increased helical content and protease resistance, and in the study on lasioglossin III and melectin, it was found that the SPs exhibited a remarkable increase in hemolytic activity, 25 while undesired for developing AMPs as antibiotics, this observation suggests that α-helical stabilization for such stapled and positively charged α-helical AMPs may not match with their mechanism of membrane interaction. 24 This is an interesting observation as it is well known that the largest class of AMPs is represented by positively charged linear peptides whose biological activity is closely linked to their propensity to become amphipathic helices upon interaction with the negatively charged surface of the bacterial cell membrane.…”

Section: Generating Cell Permeabilitymentioning

confidence: 99%