Vancomycin Resistance Is Overcome by Conjugation of Polycationic Peptides

Umstätter, Florian; Domhan, Cornelius; Hertlein, Tobias; Ohlsen, Knut; Mühlberg, Eric; Kleist, Christian; Zimmermann, Stefan; Beijer, Barbro; Klika, Karel D.; Haberkorn, Uwe; Mier, Walter; Uhl, Philipp

doi:10.1002/anie.202002727

Cited by 62 publications

(98 citation statements)

References 24 publications

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“…Hydrophilic polypeptides (e.g., XTEN and PAS) have also gained much interest in recent years as alternatives to polymers for protein conjugation [26], though no examples of AMP conjugation have yet been published. Recently, short polycationic hexa-arginine polypeptides were conjugated to vancomycin to bypass multiple modes of vancomycin resistance, accompanied by a 1000-fold increase in antibacterial activity [142]. The peptide conjugates demonstrated efficacy in vivo along with improved biodistribution and excretion profiles compared to free vancomycin.…”

Section: Polypeptidesmentioning

confidence: 99%

Towards Robust Delivery of Antimicrobial Peptides to Combat Bacterial Resistance

2020

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Antimicrobial peptides (AMPs), otherwise known as host defence peptides (HDPs), are naturally occurring biomolecules expressed by a large array of species across the phylogenetic kingdoms. They have great potential to combat microbial infections by directly killing or inhibiting bacterial activity and/or by modulating the immune response of the host. Due to their multimodal properties, broad spectrum activity, and minimal resistance generation, these peptides have emerged as a promising response to the rapidly concerning problem of multidrug resistance (MDR). However, their therapeutic efficacy is limited by a number of factors, including rapid degradation, systemic toxicity, and low bioavailability. As such, many strategies have been developed to mitigate these limitations, such as peptide modification and delivery vehicle conjugation/encapsulation. Oftentimes, however, particularly in the case of the latter, this can hinder the activity of the parent AMP. Here, we review current delivery strategies used for AMP formulation, focusing on methodologies utilized for targeted infection site release of AMPs. This specificity unites the improved biocompatibility of the delivery vehicle with the unhindered activity of the free AMP, providing a promising means to effectively translate AMP therapy into clinical practice.

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Section: Polypeptidesmentioning

confidence: 99%

Towards Robust Delivery of Antimicrobial Peptides to Combat Bacterial Resistance

2020

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“…This effect improved when a conjugate of vancomycin with cationic AMP, known as FU002, was used. This conjugate made it possible to drastically decrease the MIC values in several Staphylococcus aureus methicillin-resistant (MRSA) strains, increasing its effect 1000 times and achieving a profile of controlled biodistribution [ 41 ]. For an in-depth review of glycopeptide-resistant bacteria, see Blaskovich et al [ 39 ].…”

Section: Critical Bacterial Resistancementioning

confidence: 99%

Challenge in the Discovery of New Drugs: Antimicrobial Peptides against WHO-List of Critical and High-Priority Bacteria

et al. 2021

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Bacterial resistance has intensified in recent years due to the uncontrolled use of conventional drugs, and new bacterial strains with multiple resistance have been reported. This problem may be solved by using antimicrobial peptides (AMPs), which fulfill their bactericidal activity without developing much bacterial resistance. The rapid interaction between AMPs and the bacterial cell membrane means that the bacteria cannot easily develop resistance mechanisms. In addition, various drugs for clinical use have lost their effect as a conventional treatment; however, the synergistic effect of AMPs with these drugs would help to reactivate and enhance antimicrobial activity. Their efficiency against multi-resistant and extensively resistant bacteria has positioned them as promising molecules to replace or improve conventional drugs. In this review, we examined the importance of antimicrobial peptides and their successful activity against critical and high-priority bacteria published in the WHO list.

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“…To exclude potential toxicological effects of novel peptides, cytotoxicity studies of C11-Pep19-short and Pep19-4LF were performed using a colorimetric viability assay according to Umstätter et al [27]. Therefore, human embryonic kidney cells (HEK 293) and human liver cancer cells (HepG2) were used.…”

Section: Hemolysis and Cytotoxicity Assaymentioning

confidence: 99%

Fatty Acid Conjugation Leads to Length-Dependent Antimicrobial Activity of a Synthetic Antibacterial Peptide (Pep19-4LF)

et al. 2020

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The increasing number of infections caused by multidrug-resistant bacteria requires an intensified search for new antibiotics. Pep19-4LF is a synthetic antimicrobial peptide (GKKYRRFRWKFKGKLFLFG) that was previously designed with the main focus on high antimicrobial activity. The hydrophobic motif, LFLFG, was found to be essential for antimicrobial activity. However, this motif shows several limitations such as aggregation in biological media, low solubility, and small yields in peptide synthesis. In order to obtain more appropriate peptide characteristics, the hydrophobic motif was replaced with fatty acids. For this purpose, a shortened variant of Pep19-4LF (Pep19-short; GKKYRRFRWKFKGK) was synthesized and covalently linked to saturated fatty acids of different chain lengths. The peptide conjugates were tested with respect to their antibacterial activity by microdilution experiments on different bacterial strains. The length of the fatty acid was found to be directly correlated to the antimicrobial activity up to an ideal chain length (undecanoic acid, C11:0). This conjugate showed high antimicrobial activity in absence of toxicity. Time–kill studies revealed a fast and bactericidal mode of action. Furthermore, the first in vivo experiments of the conjugate in rodents demonstrated pharmacokinetics appropriate for application as a drug. These results clearly indicate that the hydrophobic motif of the peptide can be replaced by a single fatty acid of medium length, simplifying the design of this antimicrobial peptide while retaining high antimicrobial activity in the absence of toxicity.

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Vancomycin Resistance Is Overcome by Conjugation of Polycationic Peptides

Cited by 62 publications

References 24 publications

Towards Robust Delivery of Antimicrobial Peptides to Combat Bacterial Resistance

Towards Robust Delivery of Antimicrobial Peptides to Combat Bacterial Resistance

Challenge in the Discovery of New Drugs: Antimicrobial Peptides against WHO-List of Critical and High-Priority Bacteria

Fatty Acid Conjugation Leads to Length-Dependent Antimicrobial Activity of a Synthetic Antibacterial Peptide (Pep19-4LF)

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