No abstract

The rise of antimicrobial resistance poses a substantial threat to our health system, and, hence, development of drugs against novel targets is urgently needed. The natural peptide thanatin kills Gram-negative bacteria by targeting proteins of the lipopolysaccharide transport (Lpt) machinery. Using the thanatin scaffold together with phenotypic medicinal chemistry, structural data, and a target-focused approach, we developed antimicrobial peptides with drug-like properties. They exhibit potent activity against Enterobacteriaceae both in vitro and in vivo while eliciting low frequencies of resistance. We show that the peptides bind LptA of both wild-type and thanatin-resistant Escherichia coli and Klebsiella pneumoniae strains with low-nanomolar affinities. Mode of action studies revealed that the antimicrobial activity involves the specific disruption of the Lpt periplasmic protein bridge.

Ferroelectric thin films are investigated for their potential in photovoltaic (PV) applications, owing to their high open-circuit voltage and switchable photovoltaic effect. The direction of the ferroelectric polarization can control the sign of the photocurrent through the ferroelectric layer, theoretically allowing for 100 percent switchability of the photocurrent with the polarization, which is particularly interesting for photo-ferroelectric memories. However, the quantitative relationship between photocurrent and polarization remains little studied. In this work, a careful investigation of the polarization-dependent photocurrent of epitaxial Pb(Zr,Ti)O3 thin films has been carried out, and has provided a quantitative determination of the unswitchable part of ferroelectric polarization. These results represent a systematic approach to study and optimize the switchability of photocurrent, and more broadly to get important insights on the ferroelectric behavior in all types of ferroelectric layers in which pinned polarization is difficult to investigate.

The large switchable ferroelectric polarization and lead-free composition of BiFeO3 make it a promising candidate as an active material in numerous applications, in particular, in micro-electro-mechanical systems (MEMS) when BiFeO3 is integrated in a thin film form on a silicon substrate. Here, 200-nm-thick Mn-doped BiFeO3 thin films have been epitaxially grown on a SrRuO3/SrTiO3/Si substrate and patterned into microcantilevers as prototype device structures for piezoelectric actuation. The devices demonstrate excellent ferroelectric response with a remanent polarization of 55  μC/cm2. The epitaxial BiFeO3 MEMS exhibit very high piezoelectric response with transverse piezoelectric coefficient d31 reaching 83 pm/V. The BiFeO3 cantilevers show larger electromechanical performance (the ratio of curvature/electric field) than that of state-of-art piezoelectric cantilevers, including well-known PZT (Pb(Zr,Ti)O3) and the hyper-active PMN–PT (Pb(Mg1/3Nb2/3)O3-PbTiO3). In addition, the piezoelectricity in BiFeO3 MEMS is found to depend on the ferroelectric polarization direction, which could originate from the flexoelectric effect and be exploited to further enhance the electromechanical performance of the devices. These results could potentially lead to a replacement of lead-based piezoelectrics by BiFeO3 in many microdevices.

The rapid rise of multi-resistant bacteria poses a significant threat to our health system. The development of drugs against novel targets is urgently needed to replenish the clinical arsenal with effective antibiotics. The naturally occurring peptide thanatin kills Gram-negative bacteria by targeting the periplasmic protein bridge, in particular the lipopolysaccharide transport protein A (LptA). Using the thanatin scaffold together with phenotypic medicinal chemistry and a target-focused approach, we developed potent antimicrobial macrocyclic peptides with drug-like properties that exhibited low frequencies for development of resistance both in vitro and in vivo. Binding affinities to Escherichia coli LptA of the thanatin analogs correlated well with minimal inhibitory concentrations for both parent and thanatin-resistant E. coli strains. Mode of action studies revealed that the antimicrobial activity of the antibiotics involves the specific disruption of the periplasmic Lpt protein bridge. Our studies validate the Lpt protein bridge as a novel target for macrocyclic peptide antibiotics that can avoid current mechanisms of drug resistance. The peptides warrant further preclinical and clinical studies addressing WHO priority 1 carbapenem-resistant Enterobacteriaceae, in particular for Klebsiella pneumoniae lung infections.