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.
Subject(s)
Escherichia coli Proteins , Peptidomimetics , Enterobacteriaceae , Lipopolysaccharides , Peptidomimetics/pharmacology , Escherichia coli , Anti-Bacterial Agents/pharmacology , Carrier ProteinsABSTRACT
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% 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)O3thin 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.