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Multidrug-resistant bacteria represent one of the most important health care problems worldwide. While there are numerous drugs available for standard therapy, there are only a few compounds capable of serving as a last resort for severe infections. Therefore, approaches to control multidrug-resistant bacteria must be implemented. Here, a strategy of reactivating the established glycopeptide antibiotic vancomycin by structural modification with polycationic peptides and subsequent fatty acid conjugation to overcome the resistance of multidrug-resistant bacteria was followed. This study especially focuses on the structure–activity relationship, depending on the modification site and fatty acid chain length. The synthesized conjugates showed high antimicrobial potential on vancomycin-resistant enterococci. We were able to demonstrate that the antimicrobial activity of the vancomycin-lipopeptide conjugates depends on the chain length of the attached fatty acid. All conjugates showed good cytocompatibility in vitro and in vivo. Radiolabeling enabled the in vivo determination of pharmacokinetics in Wistar rats by molecular imaging and biodistribution studies. An improved biodistribution profile in comparison to unmodified vancomycin was observed. While vancomycin is rapidly excreted by the kidneys, the most potent conjugate shows a hepatobiliary excretion profile. In conclusion, these results demonstrate the potential of the structural modification of already established antibiotics to provide highly active compounds for tackling multidrug-resistant bacteria.

In this study, the potential of liposomes containing tetraether lipids (TELs) and cell‐penetrating peptides (CPPs) as a platform technology for oral delivery of peptides, using the glucagon‐like peptide 1 (GLP‐1) analogs semaglutide, exenatide, and dulaglutide as model compounds, was investigated. As this technology was proven effective in vitro and in vivo in mice and dogs for a small, hydrophilic glycopeptide drug (vancomycin) before, the focus of this study was to evaluate the applicability for peptide therapeutics with higher molecular weight (exenatide–4186.8 Da, semaglutide–4113.6 Da, and dulaglutide–59670.6 Da) and different physico‐chemical properties (semaglutide). For this purpose, liposomal formulations were prepared by dual centrifugation and characterized by size, polydispersity index, zeta potential, morphology, and encapsulation efficiency. All GLP‐1 analogs liposomal formulations revealed promising liposomal characteristics and were subsequently investigated with respect to uptake on colon‐carcinoma‐2 (CaCo‐2) cells and biocompatibility. Besides the high biocompatibility, a highly increased uptake of all three GLP‐1 analogs encapsulated into the liposomes containing TELs and CPPs in comparison to the free compound could be demonstrated on CaCo‐2 cells. These findings highlight the great potential of this liposomal technology for oral delivery of peptide therapeutics in general. Liposomes functionalized with tetraether lipids and cell‐penetrating peptides are explored as a platform technology for oral peptide delivery. Therefore, peptide drugs (GLP‐1 analogs) with different sizes and physicochemical properties are used as model drugs. The liposomes show favorable characteristics and increased cellular uptake by a simulated intestinal epithelium.

As multidrug-resistant bacteria represent a concerning burden, experts insist on the need for a dramatic rethinking on antibiotic use and development in order to avoid a post-antibiotic era. New and rapidly developable strategies for antimicrobial substances, in particular substances highly potent against multidrug-resistant bacteria, are urgently required. Some of the treatment options currently available for multidrug-resistant bacteria are considerably limited by side effects and unfavorable pharmacokinetics. The glycopeptide vancomycin is considered an antibiotic of last resort. Its use is challenged by bacterial strains exhibiting various types of resistance. Therefore, in this study, highly active polycationic peptide-vancomycin conjugates with varying linker characteristics or the addition of PEG moieties were synthesized to optimize pharmacokinetics while retaining or even increasing antimicrobial activity in comparison to vancomycin. The antimicrobial activity of the novel conjugates was determined by microdilution assays on susceptible and vancomycin-resistant bacterial strains. VAN1 and VAN2, the most promising linker-modified derivatives, were further characterized in vivo with molecular imaging and biodistribution studies in rodents, showing that the linker moiety influences both antimicrobial activity and pharmacokinetics. Encouragingly, VAN2 was able to undercut the resistance breakpoint in microdilution assays on vanB and vanC vancomycin-resistant enterococci. Out of all PEGylated derivatives, VAN:PEG1 and VAN:PEG3 were able to overcome vanC resistance. Biodistribution studies of the novel derivatives revealed significant changes in pharmacokinetics when compared with vancomycin. In conclusion, linker modification of vancomycin-polycationic peptide conjugates represents a promising strategy for the modulation of pharmacokinetic behavior while providing potent antimicrobial activity.

Antibiotic‐resistant enterococci represent a significant global health challenge. Unfortunately, most β‐lactam antibiotics are not applicable for enterococcal infections due to intrinsic resistance. To extend their antimicrobial spectrum, polycationic peptides are conjugated to examples from each of the four classes of β‐lactam antibiotics. Remarkably, the β‐lactam–peptide conjugates gained an up to 1000‐fold increase in antimicrobial activity against vancomycin‐susceptible and vancomycin‐resistant enterococci. Even against β‐lactam‐resistant Gram‐negative strains, the conjugates are found to be effective despite their size exceeding the exclusion volume of porins. The extraordinary gain of activity can be explained by an altered mode of killing. Of note, the conjugates showed a concentration‐dependent activity in contrast to the parent β‐lactam antibiotics that exhibited a time‐dependent mode of action. In comparison to the parent β‐lactams, the conjugates showed altered affinities to the penicillin‐binding proteins. Furthermore, it is found that peptide conjugation also resulted in a different elimination route of the compounds when administered to rodents. In mice systemically infected with vancomycin‐resistant enterococci, treatment with a β‐lactam–peptide conjugate reduced bacterial burden in the liver compared to its originator. Therefore, peptide modification of β–lactam antibiotics represents a promising platform strategy to broaden their efficacy spectrum, particularly against enterococci. Novel potent compounds are urgently required for the treatment of antibiotic‐resistant bacteria. Conjugation of polycationic peptides to β‐lactam antibiotics extends their efficacy spectrum against enterococci. The β‐lactam–peptide conjugates show significant differences in mechanism and biodistribution compared to their originators. Due to their high potency, the β‐lactam–peptide conjugates can serve as an alternative treatment option for severe enterococcal infections.

Background Even though the transition from adolescence to adulthood is a vulnerable and crucial period for young individuals with chronic conditions, it remains poorly studied in obesity. We comprehensively characterized the transition of children with overweight/obesity from childhood to adult care. Methods Data from an adulthood follow-up of the Leipzig childhood obesity cohort ( N  = 209, mean age at follow-up 24.9 years) were analyzed and related to the respective childhood data. Assessments comprised anthropometrics, oral glucose tolerance testing, carotid ultrasonography, 24 h blood pressure monitoring, liver elastography and questionnaires on psychosocial background, quality of life and transition process. Results Here we show that childhood onset overweight/obesity persists in 93.3% until adulthood. However, most patients (55.6%) who move into a higher BMI category during transition still report that things are going better with their weight during adulthood. Complications are frequent among young adults (overall 83.7%, (pre)diabetes 11.4%, hypertension 24.5%, elevated intima-media thickness 82.2%, fatty liver disease 10.2%, regular intake of medication 45%) and deteriorate with progressing weight gain from childhood to adulthood. 87% of adults have not been aware of one or more of these complications before. Most participants report physical complaints (57.3%) and symptoms of depression/anxiety (52.0%). The majority (94.3%) lose contact with specialized obesity care during transition with lack of knowledge being the most frequent reason. Instead, general practitioners are regularly consulted by 50.7%, but obesity is seldom addressed as a topic (22.6%). Better management of the transition process is desired by 26.7% of participants. Conclusions Children with overweight/obesity carry a substantial health burden into adulthood which is often not perceived. Structured transition approaches are needed to address obesity as a chronic condition. Plain language summary Young people with obesity often continue to have weight issues into adulthood, however they have been poorly followed so far. In our study, we conducted a follow-up of children with obesity at young adulthood. We revealed that health complications such as diabetes, high blood pressure, and fatty liver disease are common, yet many remain unaware. Many also experience physical discomfort and mental health struggles. Most lose contact with obesity specialists, relying instead on general doctors, who rarely discuss obesity. A quarter of participants wanted better support during the transition to adulthood. The study highlights the need for structured programs to help manage obesity as a long-term condition. Riedel et al. follow up children with obesity when they become young adults. Although obesity persists in most cases with serious complications already present, most participants do not accurately perceive their health burden and have lost contact with the healthcare system.

A popular way to analyze resting-state electroencephalography (EEG) and magneto encephalography (MEG) data is to treat them as a functional network in which sensors are identified with nodes and the interaction between channel time series and the network connections. Although conceptually appealing, the network-theoretical approach to sensor-level EEG and MEG data is challenged by the fact that EEG and MEG time series are mixtures of source activity. It is, therefore, of interest to assess the relationship between functional networks of source activity and the ensuing sensor-level networks. Since these topological features are of high interest in experimental studies, we address the question of to what extent the network topology can be reconstructed from sensor-level functional connectivity (FC) measures in case of MEG data. Simple simulations that consider only a small number of regions do not allow to assess network properties; therefore, we use a diffusion magnetic resonance imaging-constrained whole-brain computational model of resting-state activity. Our motivation lies behind the fact that still many contributions found in the literature perform network analysis at sensor level, and we aim at showing the discrepancies between source- and sensor-level network topologies by using realistic simulations of resting-state cortical activity. Our main findings are that the effect of field spread on network topology depends on the type of interaction (instantaneous or lagged) and leads to an underestimation of lagged FC at sensor level due to instantaneous mixing of cortical signals, instantaneous interaction is more sensitive to field spread than lagged interaction, and discrepancies are reduced when using planar gradiometers rather than axial gradiometers. We, therefore, recommend using lagged interaction measures on planar gradiometer data when investigating network properties of resting-state sensor-level MEG data.