g Gram-negative bacteria cause approximately 70% of the infections in intensive care units. A growing number of bacterial isolates responsible for these infections are resistant to currently available antibiotics and to many in development. Most agents under development are modifications of existing drug classes, which only partially overcome existing resistance mechanisms. Therefore, new classes of Gram-negative antibacterials with truly novel modes of action are needed to circumvent these existing resistance mechanisms. We have previously identified a new a way to inhibit an aminoacyl-tRNA synthetase, leucyl-tRNA synthetase (LeuRS), in fungi via the oxaborole tRNA trapping (OBORT) mechanism. Herein, we show how we have modified the OBORT mechanism using a structure-guided approach to develop a new boron-based antibiotic class, the aminomethylbenzoxaboroles, which inhibit bacterial leucyl-tRNA synthetase and have activity against Gram-negative bacteria by largely evading the main efflux mechanisms in Escherichia coli and Pseudomonas aeruginosa. The lead analogue, AN3365, is active against Gram-negative bacteria, including Enterobacteriaceae bearing NDM-1 and KPC carbapenemases, as well as P. aeruginosa. This novel boronbased antibacterial, AN3365, has good mouse pharmacokinetics and was efficacious against E. coli and P. aeruginosa in murine thigh infection models, which suggest that this novel class of antibacterials has the potential to address this unmet medical need.

a b s t r a c tSpecific molecular recognition is assumed to require a well-defined set of contacts and devoid of conformational and interaction ambiguities. Growing experimental evidence demonstrates however, that structural multiplicity or dynamic disorder can be retained in protein complexes, termed as fuzziness. Fuzzy regions establish alternative contacts between specific partners usually via transient interactions. Nature often tailors the dynamic properties of these segments via post-translational modifications or alternative splicing to fine-tune affinity. Most experimentally characterized fuzzy complexes are involved in regulation of gene-expression, signal transduction and cell-cycle regulation. Fuzziness is also characteristic to viral protein complexes, cytoskeleton structure, and surprisingly in a few metabolic enzymes. A plausible role of fuzzy complexes in increasing half-life of intrinsically disordered proteins is also discussed.

a b s t r a c tWe have used boron-based molecules to create novel, competitive, reversible inhibitors of phosphodiesterase 4 (PDE4). The co-crystal structure reveals a binding configuration which is unique compared to classical catechol PDE4 inhibitors, with boron binding to the activated water in the bimetal center. These phenoxybenzoxaboroles can be optimized to generate submicromolar potency enzyme inhibitors, which inhibit TNF-a, IL-2, IFN-c, IL-5 and IL-10 activities in vitro and show safety and efficacy for topical treatment of human psoriasis. They provide a valuable new route for creating novel potent anti-PDE4 inhibitors.

Edited by Wilhelm JustProteins may undergo adaptive structural transitions to accommodate to their cellular milieu and respond to external signals. Modulation of conformational ensembles can rewire the intra-or intermolecular interaction networks and shift between different functional states. Adaptive conformational transitions are associated with protein fuzziness, which enables (a) rewiring interaction networks via alternative motifs, (b) new functional features via allosteric motifs, (c) functional switches upon post-translational modifications, or (d) regulation of higher-order organizations. We propose that all these contextdependent functional changes are intertwined with structural multiplicity or dynamic disorder in protein assemblies and can only be described by stochastic structure-function relationships.

Green fluorescent aggregates of diphenylpyrimidinone–salicylideneamine show AIE + ESIPT in 99% H2O:CH3CN for the visualization of fingerprints on aluminium, steel, glass, ceramic tile and metal coin surfaces.