The Multifaceted Antibacterial Mechanisms of the Pioneering Peptide Antibiotics Tyrocidine and Gramicidin S

Wenzel, Michaela; Rautenbach, Marina; Vosloo, J. Arnold; Siersma, Tjalling; Aisenbrey, Christopher; Zaitseva, Ekaterina; Laubscher, Wikus Ernst; Rensburg, Wilma van; Behrends, Jan C.; Bechinger, Burkhard; Hamoen, Leendert W.

doi:10.1128/mbio.00802-18

Cited by 92 publications

(141 citation statements)

References 91 publications

(147 reference statements)

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“…In fact, there Antibiotics 2020, 9, 17 5 of 21 is a remarkable consensus in the literature that membrane depolarization and ion leakage only occur at high concentrations, typically much higher than the MIC and often bacteriolytic, and prolonged treatment times of at least 30 to 60 min. This is in sharp contrast to typical pore-forming molecules, which cause near-instantaneous depolarization and intracellular content leakage at their MICs [65][66][67][68][69][70], or even slower carrier ionophores, which still achieve 100% ion leakage within a few minutes [66].…”

Section: Pore Formation In Vivomentioning

confidence: 78%

“…While it was first assumed that MreB establishes RIFs, it is now known that it is needed for RIF distribution at the long axis of the cell, but not for their generation [67]. Rather, MreB filament formation and dynamics depend on the presence of lipid II [108], explaining why MurG depletion diminishes these domains [104].…”

Section: Does Daptomycin Form Domains With Fluid Lipid Domains (Rifs)mentioning

confidence: 99%

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More Than a Pore: A Current Perspective on the In Vivo Mode of Action of the Lipopeptide Antibiotic Daptomycin

Gray

Wenzel

2020

Antibiotics

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Daptomycin is a cyclic lipopeptide antibiotic, which was discovered in 1987 and entered the market in 2003. To date, it serves as last resort antibiotic to treat complicated skin infections, bacteremia, and right-sided endocarditis caused by Gram-positive pathogens, most prominently methicillin-resistant Staphylococcus aureus. Daptomycin was the last representative of a novel antibiotic class that was introduced to the clinic. It is also one of the few membrane-active compounds that can be applied systemically. While membrane-active antibiotics have long been limited to topical applications and were generally excluded from systemic drug development, they promise slower resistance development than many classical drugs that target single proteins. The success of daptomycin together with the emergence of more and more multi-resistant superbugs attracted renewed interest in this compound class. Studying daptomycin as a pioneering systemic membrane-active compound might help to pave the way for future membrane-targeting antibiotics. However, more than 30 years after its discovery, the exact mechanism of action of daptomycin is still debated. In particular, there is a prominent discrepancy between in vivo and in vitro studies. In this review, we discuss the current knowledge on the mechanism of daptomycin against Gram-positive bacteria and try to offer explanations for these conflicting observations.

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Section: Pore Formation In Vivomentioning

confidence: 78%

Section: Does Daptomycin Form Domains With Fluid Lipid Domains (Rifs)mentioning

confidence: 99%

More Than a Pore: A Current Perspective on the In Vivo Mode of Action of the Lipopeptide Antibiotic Daptomycin

Gray

Wenzel

2020

Antibiotics

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“…Recently, it has been shown that the activity of the tyrocidines is more complex than merely the result of membranolytic activity because it was observed that membrane proteins involved in peptidoglycan synthesis are influenced by tyrocidine action . Evidence has also been accumulating that the tyrocidines interact with a variety of saccharides, potentiating their activity.…”

Section: Introductionmentioning

confidence: 99%

Tyrocidine A interactions with saccharides investigated by CD and NMR spectroscopies

Juhl

Rensburg

Bossis

et al. 2019

Journal of Peptide Science

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Tyrocidines are a family of cyclic decapeptides produced by the soil bacterium, Brevibacillus parabrevis. These antibiotic peptides can be used to prevent infections in agriculture and food industry but also to prepare antimicrobial lozenges, creams, and dressings for medical applications. It has been observed that the tyrocidines interact with saccharides such as cellulose from their soil environment, as well as sugars in culture media and glycans in fungal cell walls. Here, we investigated the interactions of tyrocidines with glucose, sucrose, and cellotetraose (as cellulose model) in a quantitative fashion utilising CD and NMR spectroscopy. The CD and NMR spectra of tyrocidine A (TrcA) were analysed as a function of solvent composition, and the spectral properties agree with the formation of oligomeric structures that are governed by β-sheet secondary structures once the acetonitrile content of the solvent is increased. Saccharides seem to also induce TrcA spectral changes reverting those induced by organic solvents. The CD spectral changes of TrcA in the presence of glucose agree with new ordered H-bonding, possibly β-sheet structures. The amides involved in intramolecular H-bonding remained largely unaffected by the environmental changes. In contrast, amides exposed to the exterior and/or involved in TrcA intermolecular association show the largest 1 H chemical shift changes. CD and NMR spectroscopic investigations correlated well with TrcAglucose interactions characterized by a dissociation constant around 200 μM. Interestingly, the association of cellotetraose corresponds closely to the additive effect from four glucose moieties, while a much higher dissociation constant was observed for sucrose. Similar trends to TrcA for binding to the three saccharides were observed for the analogous tyrocidines, tyrocidine B, and tyrocidine C. These results therefore indicate that the tyrocidine interactions with the glucose monosaccharide unit are fairly specific and reversible.

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“…Wir untersuchten zunächst, ob 1 die Integrität der Vesikel beeinflusst. Dazu wurde die Fähigkeit von 1 , den Fluoreszenzfarbstoff Carboxyfluorescein (CF) freizusetzen, mit der des cyclischen Dekapeptids Gramicidin S ( 25 ), welches eine Membrandestabilisierung bewirkt, verglichen. Der Farbstoff wird in die Vesikel in einer sich selbst löschenden Konzentration (100 m m ) eingeschlossen und der Austritt bewirkt eine Zunahme der Fluoreszenz.…”

Section: Methodsunclassified

Synthetische Analoga zeigen die essentiellen Strukturmotive von Lugdunin und seinen Protonentransport

et al. 2019

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Lugdunin, ein neues Thiazolidin-Cyclopeptid, weist gegenüber Methicillin-resistentem Staphylococcus aureus (MRSA) antimikrobielle Wirkung im mikromolaren Bereich auf.Fürdie Untersuchung von Struktur-Aktivitätsbeziehungen (SAR) wurden synthetische Alanin-und Stereo-Derivate sowie Peptide mit modifiziertem Thiazolidinring auf ihre antimikrobielle Aktivitätg etestet. Sowohl das Thiazolidin als auch die d-, l-alternierende Konfiguration stellen essentielle Strukturmotive dar.B emerkenswert ist die identischeA ktivitätd es Enantiomers,w as eine stereospezifische Wechselwirkung mit einem Zielmoleküla usschließt. Die antibakterielle Wirkung korreliert stark mit dem Einbrechen des Membranpotentials von S. aureus.Lugdunin gleichtpH-Gradienten in künstlichen Membranvesikeln unter Erhalt der Membranintegritäta us. Der Wirkmechanismus (MoA) beruht somit auf Protonentransport. Der Einbau eines zusätzlichen Tryptophans oder einer Propargylfunktion erweitert die Diversitätd ieser neuen Substanzklasse der Thiazolidin-Cyclopeptide.

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The Multifaceted Antibacterial Mechanisms of the Pioneering Peptide Antibiotics Tyrocidine and Gramicidin S

Cited by 92 publications

References 91 publications

More Than a Pore: A Current Perspective on the In Vivo Mode of Action of the Lipopeptide Antibiotic Daptomycin

More Than a Pore: A Current Perspective on the In Vivo Mode of Action of the Lipopeptide Antibiotic Daptomycin

Tyrocidine A interactions with saccharides investigated by CD and NMR spectroscopies

Synthetische Analoga zeigen die essentiellen Strukturmotive von Lugdunin und seinen Protonentransport

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