Combining Topology and Sequence Design for the Discovery of Potent Antimicrobial Peptide Dendrimers against Multidrug‐Resistant <i>Pseudomonas aeruginosa</i>

Stach, Michaela; Siriwardena, Thissa N.; Köhler, Thilo; Delden, Christian van; Darbre, Tamis; Reymond, Jean‐Louis

doi:10.1002/ange.201409270

Cited by 38 publications

(49 citation statements)

References 42 publications

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“…We identified our first membrane disrupting antimicrobial peptide dendrimer (AMPD) by screening a combinatorial library using an off-bead Bacillus subtilis growth inhibition assay, [22 -24] which pointed to dendrimer bH1, a third generation (G3) dendrimer containing single hydrophobic residues in its branches and eight positive charges at the N-termini ( Figure 1, Table 1). [25,26] We then exploited multivalency and sequence design to obtain AMPD G3KL, [27] a G3 dendrimer featuring a lysine-leucine (KL) dipeptide in its G0, G1, G2, and G3 branches, a sequence element frequently encountered in linear antimicrobial peptides (AMPs). [28][29][30][31][32] Compared to our original AMPD bH1, extending single amino acid branches to dipeptides in all generations increased the number of positive charges and hydrophobic groups as means to confer stronger antimicrobial activity.…”

Section: Introductionmentioning

confidence: 99%

Antimicrobial Peptide Dendrimer Chimera

Siriwardena

Lüscher

Köhler

et al. 2019

Helvetica Chimica Acta

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We recently reported the discovery of antimicrobial peptide dendrimers (AMPDs) acting by a membrane‐disruptive mechanism against multidrug resistant pathogenic bacteria. Here, we combined amino acid sequence elements from different AMPDs with different activity profiles to form AMPD chimeras. By joining the outer branches of TNS18, an AMPD active against Pseudomonas aeruginosa, Acinetobacter baumannii and methicillin resistant Staphylococcus aureus, with the core of T7, another AMPD active against P. aeruginosa, A. baumannii and Klebsiella pneumoniae, we obtained AMPD chimera DC5 displaying all previously observed activities while retaining a similar mechanism of action. These experiments show that chimera design represents a useful strategy to improve the properties of AMPDs.

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Section: Introductionmentioning

confidence: 99%

Antimicrobial Peptide Dendrimer Chimera

Siriwardena

Lüscher

Köhler

et al. 2019

Helvetica Chimica Acta

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“…They kill microorganisms using various strategies that include membrane disruption as the chief mechanism, apart from having downstream intracellular targets (14). They offer themselves as attractive substitutes for conventional small molecule drugs in view of their membrane disruption properties that allow them to circumvent the development of resistance in microbial targets (3,(15)(16)(17)(18). A number of these naturally occurring molecules are endowed with antimicrobial activities; however, their use is restricted to topical applications owing to their cytotoxicity (19).…”

Section: Introductionmentioning

confidence: 99%

Mode of Action of a Designed Antimicrobial Peptide: High Potency against Cryptococcus neoformans

Datta¹,

Yadav

Ghosh³

et al. 2016

Biophysical Journal

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There is a significant need for developing compounds that kill Cryptococcus neoformans, the fungal pathogen that causes meningoencephalitis in immunocompromised individuals. Here, we report the mode of action of a designed antifungal peptide, VG16KRKP (VARGWKRKCPLFGKGG) against C. neoformans. It is shown that VG16KRKP kills fungal cells mainly through membrane compromise leading to efflux of ions and cell metabolites. Intracellular localization, inhibition of in vitro transcription, and DNA binding suggest a secondary mode of action for the peptide, hinting at possible intracellular targets. Atomistic structure of the peptide determined by NMR experiments on live C. neoformans cells reveals an amphipathic arrangement stabilized by hydrophobic interactions among A2, W5, and F12, a conventional folding pattern also known to play a major role in peptide-mediated Gram-negative bacterial killing, revealing the importance of this motif. These structural details in the context of live cell provide valuable insights into the design of potent peptides for effective treatment of human and plant fungal infections.

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“…Recently, it has been reported that the combination of various topology and sequence designs allowed for the discovery of potent antimicrobial peptide dendrimers (AMPDs) against MDR P. aeruginosa 18 . Indeed, the activities of the AMPDs, namely G3KL and G3RL ( Fig.…”

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confidence: 99%

Anti-Microbial Dendrimers against Multidrug-Resistant P. aeruginosa Enhance the Angiogenic Effect of Biological Burn-wound Bandages

Abdel-Sayed

Kaeppli

Siriwardena

et al. 2016

Sci Rep

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Multi-drug resistant Pseudomonas aeruginosa has increased progressively and impedes further regression in mortality in burn patients. Such wound infections serve as bacterial reservoir for nosocomial infections and are associated with significant morbidity and costs. Anti-microbial polycationic dendrimers G3KL and G3RL, able to kill multi-drug resistant P. aeruginosa, have been previously developed. The combination of these dendrimers with a class of biological bandages made of progenitor skin cells, which secrete growth factors, could positively impact wound-healing processes. However, polycations are known to be used as anti-angiogenic agents for tumor suppression. Since, neovascularization is pivotal in the healing of deep burn-wounds, the use of anti-microbial dendrimers may thus hinder the healing processes. Surprisingly, we have seen in this study that G3KL and G3RL dendrimers can have angiogenic effects. Moreover, we have shown that a dendrimer concentration ranging between 50 and 100 μg/mL in combination with the biological bandages can suppress bacterial growth without altering cell viability up to 5 days. These results show that antimicrobial dendrimers can be used in combination with biological bandages and could potentially improve the healing process with an enhanced angiogenesis.

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Combining Topology and Sequence Design for the Discovery of Potent Antimicrobial Peptide Dendrimers against Multidrug‐Resistant Pseudomonas aeruginosa

Cited by 38 publications

References 42 publications

Antimicrobial Peptide Dendrimer Chimera

Antimicrobial Peptide Dendrimer Chimera

Mode of Action of a Designed Antimicrobial Peptide: High Potency against Cryptococcus neoformans

Anti-Microbial Dendrimers against Multidrug-Resistant P. aeruginosa Enhance the Angiogenic Effect of Biological Burn-wound Bandages

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