Structure–Activity Relationship-based Optimization of Small Temporin-SHf Analogs with Potent Antibacterial Activity

André, Sónia; Washington, Shannon K; Darby, Emily; Vega, Marvin M; Filip, A; Ash, Nathaniel S; Muzikar, Katy A.; Piesse, Christophe; Foulon, Thierry; O’Leary, Daniel J.; Ladram, Ali

doi:10.1021/acschembio.5b00495

Cited by 27 publications

(51 citation statements)

References 45 publications

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“…As reported by André et al. (), various linear analogues of temporin‐SHf also adopt helical conformation in membrane‐mimetic environment. In the present report, disulfide engineering strategy was adopted to improve the stability of bioactive conformation of temporin‐SHf.…”

Section: Introductionsupporting

confidence: 53%

“…It is evident from the report of André et al. () and Mishra et al. (), Leu4 and Ile7 residues are functionally non‐critical in temporin‐SHf.…”

Section: Resultsmentioning

confidence: 95%

“…Temporin‐SHf is a broad spectrum antimicrobial peptide, devoid of hemolytic activity in the vicinity of minimal inhibitory concentration (MIC), and active on resistant bacterial strains (Abbassi et al., ; André et al., ). The bioactive conformation of temporin‐SHf is helix located at the C‐terminus of the peptide spanning from Phe3 to Phe8 residues (Abbassi et al., ; André et al., ). As reported by Abbassi et al.…”

Section: Introductionmentioning

confidence: 99%

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Disulfide engineering on temporin‐SHf: Stabilizing the bioactive conformation of an ultra‐short antimicrobial peptide

et al. 2019

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In Silico searching for short antimicrobial peptides has revealed temporin‐SHf as the short (8AA), hydrophobic, broad spectrum, and natural antimicrobial peptide. Important drawback associated with temporin‐SHf is the susceptibility of its bioactive conformation for denaturation and proteolytic degradation. In the current report, disulfide engineering strategy has been adopted to improve the stability of bioactive conformation of temporin‐SHf. The functionally non‐critical Leu4 and Ile7 residues at i and i + 3 position of helical conformation of temporin‐SHf were mutated with cysteine disulfide. Designed [L4C, I7C]temporin‐SHf was synthesized, characterized using NMR spectroscopy, and accessed for antimicrobial activity. [L4C, I7C]Temporin‐SHf adopts helical conformation from Phe3 to Phe8 in the absence of membrane‐mimetic environment and retains broad spectrum antimicrobial activity. The reduction potential of cysteine disulfide of [L4C, I7C]temporin‐SHf is −289 mV. Trypsin‐induced digestion and serum‐induced digestion have confirmed the advantage of cysteine disulfide in imparting proteolytic stability to temporin‐SHf. Disulfide‐stabilized temporin‐SHf may serve as a good model for the rational design of temporin‐SHf based antibiotics for treatment of infectious diseases.

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Section: Introductionsupporting

confidence: 53%

“…It is evident from the report of André et al. () and Mishra et al. (), Leu4 and Ile7 residues are functionally non‐critical in temporin‐SHf.…”

Section: Resultsmentioning

confidence: 95%

Section: Introductionmentioning

confidence: 99%

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Disulfide engineering on temporin‐SHf: Stabilizing the bioactive conformation of an ultra‐short antimicrobial peptide

et al. 2019

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“…We also observed a 2-fold higher leishmanicidal activity of temporins in serum-free medium. The effect of serum on antimicrobial activity has been previously noted for both SHa [29] and SHf [73]. …”

Section: Discussionmentioning

confidence: 99%

“…Membrane depolarization of S . aureus ATCC 25923 was assessed using a previously described protocol [73]. Leishmania promastigotes ( L .…”

Section: Methodsmentioning

confidence: 99%

Insight into the mechanism of action of temporin-SHa, a new broad-spectrum antiparasitic and antibacterial agent

et al. 2017

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Antimicrobial peptides (AMPs) are promising drugs to kill resistant pathogens. In contrast to bacteria, protozoan parasites, such as Leishmania, were little studied. Therefore, the antiparasitic mechanism of AMPs is still unclear. In this study, we sought to get further insight into this mechanism by focusing our attention on temporin-SHa (SHa), a small broad-spectrum AMP previously shown to be active against Leishmania infantum. To improve activity, we designed analogs of SHa and compared the antibacterial and antiparasitic mechanisms. [K3]SHa emerged as a highly potent compound active against a wide range of bacteria, yeasts/fungi, and trypanosomatids (Leishmania and Trypanosoma), with leishmanicidal intramacrophagic activity and efficiency toward antibiotic-resistant strains of S. aureus and antimony-resistant L. infantum. Multipassage resistance selection demonstrated that temporins-SH, particularly [K3]SHa, are not prone to induce resistance in Escherichia coli. Analysis of the mode of action revealed that bacterial and parasite killing occur through a similar membranolytic mechanism involving rapid membrane permeabilization and depolarization. This was confirmed by high-resolution imaging (atomic force microscopy and field emission gun-scanning electron microscopy). Multiple combined techniques (nuclear magnetic resonance, surface plasmon resonance, differential scanning calorimetry) allowed us to detail peptide-membrane interactions. [K3]SHa was shown to interact selectively with anionic model membranes with a 4-fold higher affinity (KD = 3 x 10−8 M) than SHa. The amphipathic α-helical peptide inserts in-plane in the hydrophobic lipid bilayer and disrupts the acyl chain packing via a detergent-like effect. Interestingly, cellular events, such as mitochondrial membrane depolarization or DNA fragmentation, were observed in L. infantum promastigotes after exposure to SHa and [K3]SHa at concentrations above IC50. Our results indicate that these temporins exert leishmanicidal activity via a primary membranolytic mechanism but can also trigger apoptotis-like death. The many assets demonstrated for [K3]SHa make this small analog an attractive template to develop new antibacterial/antiparasitic drugs.

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Short AntiMicrobial Peptides (SAMPs) as a class of extraordinary promising therapeutic agents

et al. 2016

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The emergence of multidrug resistant bacteria has a direct impact on global public health because of the reduced potency of existing antibiotics against pathogens. Hence, there is a pressing need for new drugs with different modes of action that can kill microorganisms. Antimicrobial peptides (AMPs) can be regarded as an alternative tool for this purpose because they are proven to have therapeutic effects with broad-spectrum activities. There are some hurdles in using AMPs as clinical candidates such as toxicity, lack of stability and high budgets required for manufacturing. This can be overcome by developing shorter and more easily accessible AMPs, the so-called Short AntiMicrobial Peptides (SAMPs) that contain between two and ten amino acid residues. These are emerging as an attractive class of therapeutic agents with high potential for clinical use and possessing multifunctional activities. In this review we attempted to compile those SAMPs that have exhibited biological properties which are believed to hold promise for the future. Copyright © 2016 European Peptide Society and John Wiley & Sons, Ltd.

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Structure–Activity Relationship-based Optimization of Small Temporin-SHf Analogs with Potent Antibacterial Activity

Cited by 27 publications

References 45 publications

Disulfide engineering on temporin‐SHf: Stabilizing the bioactive conformation of an ultra‐short antimicrobial peptide

Disulfide engineering on temporin‐SHf: Stabilizing the bioactive conformation of an ultra‐short antimicrobial peptide

Insight into the mechanism of action of temporin-SHa, a new broad-spectrum antiparasitic and antibacterial agent

Short AntiMicrobial Peptides (SAMPs) as a class of extraordinary promising therapeutic agents

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