Lysine substitutions convert a bacterial-agglutinating peptide into a bactericidal peptide that retains anti-lipopolysaccharide activity and low hemolytic activity

Abdolhosseini, Mahsa; Nandula, Seshagiri Rao; Song, Jian; Hirt, Helmut; Gorr, Sven Ulrik

doi:10.1016/j.peptides.2012.03.017

Cited by 62 publications

(106 citation statements)

References 26 publications

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“…Such AMPs include P113, which was derived from histatin 5 (Rothstein et al 2001);hLf1-11, from lactoferrin (Godoy-Gallardo et al 2014); and GL13K, from parotid secretory protein (BPIFA2; Abdolhosseini et al 2012;Balhara et al 2013;Hirt and Gorr 2013; Table 1). The goal for these peptides is to achieve strong antibacterial activity with low toxicity to mammalian cells and low ability to induce resistance in bacteria.…”

Section: Design Of Ampsmentioning

confidence: 99%

“…Thus, for the purposes of this review, we focus on recent developments in the mechanisms of antibacterial activity of cationic AMPs (Bechinger 2015) and the development of bacterial resistance to these peptides. As appropriate, the review discusses naturally occurring AMPs and modified cationic peptide designs, as exemplified by our recent development of the peptide GL13K (Abdolhosseini et al 2012).…”

Section: Models For Amp Functionmentioning

confidence: 99%

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Antimicrobial Peptides: Mechanisms of Action and Resistance

2016

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More than 40 antimicrobial peptides and proteins (AMPs) are expressed in the oral cavity. These AMPs have been organized into 6 functional groups, 1 of which, cationic AMPs, has received extensive attention in recent years for their promise as potential antibiotics. The goal of this review is to describe recent advances in our understanding of the diverse mechanisms of action of cationic AMPs and the bacterial resistance against these peptides. The recently developed peptide GL13K is used as an example to illustrate many of the discussed concepts. Cationic AMPs typically exhibit an amphipathic conformation, which allows increased interaction with negatively charged bacterial membranes. Peptides undergo changes in conformation and aggregation state in the presence of membranes; conversely, lipid conformation and packing can adapt to the presence of peptides. As a consequence, a single peptide can act through several mechanisms depending on the peptide's structure, the peptide:lipid ratio, and the properties of the lipid membrane. Accumulating evidence shows that in addition to acting at the cell membrane, AMPs may act on the cell wall, inhibit protein folding or enzyme activity, or act intracellularly. Therefore, once a peptide has reached the cell wall, cell membrane, or its internal target, the difference in mechanism of action on gram-negative and gram-positive bacteria may be less pronounced than formerly assumed. While AMPs should not cause widespread resistance due to their preferential attack on the cell membrane, in cases where specific protein targets are involved, the possibility exists for genetic mutations and bacterial resistance. Indeed, the potential clinical use of AMPs has raised the concern that resistance to therapeutic AMPs could be associated with resistance to endogenous host-defense peptides. Current evidence suggests that this is a rare event that can be overcome by subtle structural modifications of an AMP.

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Section: Design Of Ampsmentioning

confidence: 99%

Section: Models For Amp Functionmentioning

confidence: 99%

Antimicrobial Peptides: Mechanisms of Action and Resistance

2016

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“…We have recently designed the 13-amino-acid peptide GL13K, which was derived from human parotid secretory protein (PSP; BPIFA2) (8)(9)(10). PSP belongs to a family of bactericidal/permeability-increasing (BPI) fold proteins (11) that are expressed in the upper respiratory tract and oral cavity (12) and show predicted similarity to the BPI protein and lipopolysaccharide (LPS)-binding protein (LBP).…”

mentioning

confidence: 99%

“…These activities are mirrored by a 13-aminoacid peptide (GL13NH 2 ) corresponding to amino acid residues 141 to 153 of PSP. This peptide aggregates both Gram-negative and Gram-positive bacteria and binds LPS but lacks bactericidal activity (8)(9)(10). In an effort to confer bactericidal activity, charged amino acids in positions 2, 5, and 11 of GL13NH 2 were replaced by lysine residues, resulting in the peptide GL13K, with an overall positive charge of ϩ5.…”

mentioning

confidence: 99%

“…GL13K exhibits bactericidal activity but not bacterium-agglutinating activity. The peptide retains the ability to block LPS action, with low toxicity against eukaryotic cells (8,10). Recent studies on the mechanism of GL13K action indicate a carpet-like insertion in bacterial model membranes and release of bacterial membrane lipids in the form of micelles, leading to damage to the cell (13).…”

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confidence: 99%

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Antimicrobial Peptide GL13K Is Effective in Reducing Biofilms of Pseudomonas aeruginosa

Hirt

Gorr

2013

Antimicrob Agents Chemother

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105

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Human parotid secretory protein (PSP; BPIF2A) is predicted to be structurally similar to bactericidal/permeability-increasing protein and lipopolysaccharide (LPS)-binding protein. Based on the locations of known antimicrobial peptides in the latter two proteins, potential active peptides in the PSP sequence were identified. One such peptide, GL13NH 2 (PSP residues 141 to 153) was shown previously to interfere with LPS binding and agglutinate bacteria without bactericidal activity. By introducing three additional positively charged lysine residues, the peptide was converted to the novel bactericidal cationic peptide GL13K (MIC for Pseudomonas aeruginosa, 8 g/ml [5.6 M]). We investigated the antibiofilm activity of GL13K against static, monospecies biofilms of P. aeruginosa PAO1. Two-hour exposure of a 24-h biofilm to 64 g/ml (44.8 M) GL13K reduced biofilm bacteria by 10 2 , and 100 g/ml (70 M) GL13K reduced bacteria by 10 3 . Similar results could be achieved on 48-h-old biofilms. Lower concentrations of GL13K (32 g/ml [22.4 M]) were successful in reducing biofilm cell numbers in combination with tobramycin. This combination treatment also achieved total eradication of the biofilm in a majority (67.5%) of tested samples. An alanine scan of GL13K revealed the importance of the leucine residue in position six of the peptide sequence, where replacement led to a loss of antibiofilm activity, whereas the impact of replacing charged residues was less pronounced. Bacterial metalloproteases were found to partially inactivate GL13K but not a D amino acid version of the peptide.

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DNA Nanostructures in the Fight Against Infectious Diseases

Smith

Keller

2021

Advanced NanoBiomed Research

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The ongoing COVID-19 pandemic has once more led to the realization that humanity is dangerously ill prepared for fighting the threats associated with epidemic outbreaks of infectious diseases. COVID-19 is only the latest in a long list of viral diseases, including SARS, [1] MERS, [2] Zika, [3] Ebola, [4] and Nipah, [5] that emerged as severe threats to public health in the past two decades and that continue to threaten human lives. However, also diseases that have plagued humanity for centuries still present a severe burden. For instance, the 20th century has seen three influenza pandemics with death tolls in the millions [6] and the seasonal flu still kills on average an estimated 389 000 people each year. [7] Furthermore, due to the global rise of antibiotic resistance in the past few decades, bacterial infections have once again become a severe threat to human health. [8] In 2015, about 670 000 patients in the EU alone suffered from infections with antibiotic-resistant strains of eight bacterial pathogens, resulting in 33 000 deaths. [9] The situation in the US is similar, with an estimated 23 000 deaths each year as a direct result of more than 2 million multidrug-resistant infections. [10] In low-and middle-income countries with limited ability to pay for second-line drugs, antibiotic resistance results in even higher mortality rates. In 2010, about 38 000 deaths in Thailand alone were attributed to infections with only five antibiotic-resistant bacteria. [11] In India, it is estimated that about 60 000 neonatal deaths each year result from antibiotic-resistant bacterial infections. [8] More recently, the worldwide emergence of antifungal resistance has raised grave concerns as well, [12] as invasive fungal infections are responsible for at least 2 million life-threatening

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Lysine substitutions convert a bacterial-agglutinating peptide into a bactericidal peptide that retains anti-lipopolysaccharide activity and low hemolytic activity

Cited by 62 publications

References 26 publications

Antimicrobial Peptides: Mechanisms of Action and Resistance

Antimicrobial Peptides: Mechanisms of Action and Resistance

Antimicrobial Peptide GL13K Is Effective in Reducing Biofilms of Pseudomonas aeruginosa

DNA Nanostructures in the Fight Against Infectious Diseases

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