Liposomal formulation of resistance breaking vancomycin derivatives

Dr. Philipp Uhl1) and Prof. Dr. Walter Mier1)

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Dr. Philipp Uhl and Professor Dr. Walter MierHeidelberg University Hospital, Department of Nuclear Medicine, Im Neuenheimer Feld 400, 69120 Heidelberg, Germany

People involved

Ms. M.Sc. Julia Werner (PhD fellow sponsored by the PRC) – Heidelberg University Hospital (


The aim of this project is to exploit the potential of liposomal formulations to improve antibiotic therapy. While there are numerous drugs available for the therapy of bacterial infections, there are only a few compounds capable to serve as last resort for severe infections. Vancomycin is the pivotal antibiotic for the treatment of multidrug-resistant (MDR) infections caused by Gram-positive bacteria. We recently developed highly potent vancomycin-derivatives (FU002 as lead candidate) which were able to overcome vancomycin resistance.1)2) Vancomycin and FU002 suffer from low oral bioavailability and poor pharmacokinetics due to their rapid renal/hepatobiliary excretion.

Novel liposomal formulations of FU002 might enhance both its oral availability and its pharmacokinetics. As our previous findings demonstrated that cell penetrating peptide (CPP)-modification of the surface boosts oral delivery of peptide drugs, the liposomes contain CPP-phospholipid conjugates. Moreover, the liposomal formulation contains tetraether lipids (TELs) that enhance the stability in the gastrointestinal tract.3)4)5) For pharmacokinetics optimization, the liposomal formulation shall be further modified by various PEGylation strategies.

Prolonged contact between the antibiotic and biofilm-producing bacteria can be achieved by liposomes possessing a surface charge opposite to the negative surface charge of the bacterial cell wall. The cell penetrating peptides on the liposomal surface intrinsically lead to a positive charge and might therefore perfectly fulfill these requirements. The project is based on the conscientious preparation of the liposomal formulation and their subsequent physicochemical characterization followed by the determination of the antibacterial activity. The enhancement of the pharmacokinetics is monitored by molecular imaging of both the radiolabeled nanocarrier and its cargo. One of our cooperation partners can determine the in vivo efficacy in a Methicillin-resistant Staphylococcus aureus (MRSA) systemic infection mouse model.

Benefit for the community

Oral delivery of peptide drugs represents one of the research topics of “high interest and priority” for the pharmaceutical community. In preliminary studies, we could establish a highly effective liposomal formulation technology for oral delivery of peptide therapeutics. Therefore, this grant application intends to obtain a more detailed insight and understanding of this technology by formulation of a novel, highly potent antibiotic addressing also biofilm producing bacteria. Considering the emergence of multidrug-resistant bacteria, innovations in the development of new antibiotics are highly demanded. Additionally, liposomal PEGylation strategies shall be used for pharmacokinetics optimization enabling parenteral administration with reduced side-effects. Such formulation strategies can prevent the failure of potent drug candidates suffering from unfavorable characteristics.

The findings of this grant application will enable the community to use this formulation strategy with the perspective to boost the oral application of peptide drugs including novel therapeutic fields, i.e., the current task to achieve oral vaccination of large cohorts.

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Radiopharmaceutical Chemistry

Umstätter F, Domhan C, Hertlein T, Ohlsen K, Mühlberg E, Kleist C, Zimmermann S, Beijer B, Klika KD, Haberkorn U, Mier W, Uhl P, 2020
Vancomycin Resistance Is Overcome by Conjugation of Polycationic Peptides
Angew. Chem. Int. Ed. 59, 8823-8827
Mühlberg E, Umstätter F, Domhan C, Hertlein T, Ohlsen K, Krause A, Kleist C, Beijer B, Zimmermann S, Haberkorn U, Mier W, Uhl P, 2020
Vancomycin-Lipopeptide Conjugates with High Antimicrobial Activity on Vancomycin-Resistant Enterococci
Pharmaceuticals 13, 110
Uhl P, Helm F, Hofhaus G, Brings S, Kaufman C, Leotta K, Urban S, Haberkorn U, Mier W, Fricker G, 2016
A liposomal formulation for the oral application of the investigational hepatitis B drug Myrcludex B
Eur. J. Pharm. Biopharm. 103, 159-166
Uhl P, Pantze S, Storck P, Parmentier J, Witzigmann D, Hofhaus G, Huwyler J, Mier W, Fricker G, 2017
Oral delivery of vancomycin by tetraether lipid liposomes
Eur. J. Pharm. Sci. 108, 111-118
Uhl P, Sauter M, Hertlein T, Witzigmann D, Laffleur F, Hofhaus G, Fidelj V, Tursch A, Özbek S, Hopke E, Haberkorn U, Bernkop-Schnürch A, Ohlsen K, Fricker G, Mier W, 2021
Overcoming the Mucosal Barrier: Tetraether Lipid-Stabilized Liposomal Nanocarriers Decorated with Cell-Penetrating Peptides Enable Oral Delivery of Vancomycin
Adv. Therap. n/a, 2000247
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