No abstract

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.

Any organic crystal structure can be simplified to a network wherein the molecules are the nodes and the supramolecular synthons are the node connections. This approach to crystal engineering is illustrated in this paper with reference to organic structures based on the diamond network. By introducing N‚ ‚ ‚Br synthons into this network, a 2-fold-catenated structure is obtained for the 1:1 complex between hexamethylenetetramine (HMT) and CBr 4 . The use of C-H‚ ‚ ‚N mediated synthons in the same network results in the 1:2 complex of 1,3,5,7-tetrabromoadamantane (AdBr 4 ) with HMT. Further structural flexibility is achieved by the interchange of molecular and supramolecular synthons. Accordingly, the diamond-based crystal structures of tetrakis-(4-bromophenyl)methane and the 1:1 molecular complex of tetraphenylmethane and CBr 4 are very similar. This near-identity arises because of the structural equivalence of the CBr 4 molecular synthon and the Br 4 supramolecular synthon and the ability of the CBr 4 molecule to participate in Br‚ ‚ ‚phenyl interactions. In general, there is much topological correspondence between organic and inorganic crystal structures, and this can be utilized in the description of organic crystal structures as networks. Such a depiction is of much practical utility and is different from Kitaigorodskii's model which distinguishes fundamentally between molecular and crystal structure. In the network model, molecular and supramolecular synthons are interchangeable within the same network structure.

The neutron diffraction analysis of crystals of 2-ethynyladamantan-2-ol (I) provides confirmation of the presence of an unusual O−H···π hydrogen bond, together with more common O−H···O and C−H···O bonds, as proposed previously. This is first neutron analysis of an O−H···π hydrogen bond, which is shown to be short and linear, with the O−H vector clearly directed towards the mid-point (X) of the triple bond (O···X = 3.221 Å, H···X = 2.258 Å, O−H···X = 179.0°) rather than toward either of the two alkyne carbon atoms. An exceptionally short and straight C−H···O bond is also present in the network which probably owes its characteristics to a cooperative effect with an O−H···O hydrogen bond. The three types of hydrogen bond in this crystal structure link molecules to form supramolecular synthons which are defined as spatial arrangements of intermolecular interactions which incorporate the geometrical and chemical recognition features of molecules.