Challenges in the Development of a Thiol-Based Broad-Spectrum Inhibitor for Metallo-ß-Lactamases.

Pathogens, expressing metallo-ß-lactamases (MBLs), become resistant against most ß-lactam antibiotics. Besides the dragging search for new antibiotics, development of MBL inhibitors would be an alternative weapon against resistant bacterial pathogens. Inhibition of resistance enzymes could restore the antibacterial activity of ß-lactams. Various approaches to MBL inhibitors are described; among others, the promising motif of a zinc coordinating thiol moiety is very popular. Nevertheless, since the first report of a thiol-based MBL inhibitor (thiomandelic acid) in 2001, no steps in development of thiol based MBL inhibitors were reported that go beyond clinical isolate testing. In this study, we report on the synthesis and biochemical characterization of thiol-based MBL inhibitors and highlight the challenges behind the development of thiol-based compounds, which exhibit good in vitro activity toward a broad spectrum of MBLs, selectivity against human off-targets, and reasonable activity against clinical isolates.

Anti-tubercular activity of a natural stilbene and its synthetic derivatives.

Objectives: Tuberculosis (TB) and multidrug- and extensively drug-resistant TB in particular are remaining a major global health challenge and efficient new drugs against TB are needed. This study evaluated the anti-tubercular activity of a natural stilbene and its synthetic derivatives against M. tuberculosis. Methods: Isopropylstilbene and its synthetic derivatives were analyzed for their anti-tubercular activity against M. tuberculosis ATCC 27294 as well as multidrug- and extensively drug-resistant M. tuberculosis clinical isolates by using MGIT 960 instrumentation and EpiCenter software equipped with TB eXiST module. Cytotoxic effects of drug candidates were determined by a MTT dye reduction assay using A549 adenocarcinomic human alveolar basal epithelial cells. Results: Growth of M. tuberculosis ATCC 27294 was suppressed by the natural isopropylstilbene HB64 as well as synthetic derivatives DB56 and DB55 at 25 µg/ml. Growth of clinical isolates MDR and XDR M. tuberculosis was suppressed by HB64 at 100 µg/ml as well as by synthetic derivatives DB56 and DB55 at 50 µg/ml and 25 µg/ml, respectively. No anti-tubercular activity was demonstrated for synthetic derivatives DB53, EB251, and RB57 at 100 µg/ml. Toxicity in terms of IC50 values of HB64, DB55 and DB56 were 7.92 µg/ml, 12.15 µg/ml and 16.01 µg/ml, respectively. Conclusions: Synthetical derivatives of stilbene might be effective candidates as anti-tubercular drugs. However, toxicity of these substances as determined by IC50 values might limit therapeutic success in vivo. Further investigations should address lowering the toxicity for parenteral administration by remodeling stilbene derivatives.

Probing metallo-ß-lactamases with molecular fragments identified by consensus docking.

Bacterial resistance mediated by metallo-ß-lactamases (MBLs) is a major problem for the treatment of infections. An MBL inhibitor could restore the potency of ß-lactam antibiotics. Fragment-based design might deliver valuable starting points for the discovery of novel MBL inhibitors. In this study, we chose an in silico approach to search for fragments able to bind and inhibit NDM-1, VIM-1, and IMP-7. We used consensus docking to identify low molecular weight compounds from a commercially available library. Most promising compounds were evaluated in a sensitive fluorescence-based activity assay and by the orthogonal biophysical technique saturation transfer difference (STD)-NMR. (1)H-(15)N chemical shift perturbation NMR was used to confirm the reversible binding and measure the dissociation constant of the most promising compound qualifying it as a high-quality starting point for further optimization.

From a multipotent stilbene to soluble epoxide hydrolase inhibitors with antiproliferative properties.

Inspired by nature: Natural product isopropylstilbene was identified as an inhibitor of soluble epoxide hydrolase exhibiting antiproliferative properties. Following the natural product inspired design approach, a library of (E)-styryl-1H-benzo[d]imidazoles was synthesized and evaluated with recombinant enzyme and on several cancer cell lines.

Tetrakis(µ(3)-9-oxa-10-boraanthracen-10-olato)tetrakis[(diethyl ether)lithium].

The title compound, [Li(4)O(4)(C(12)H(8)BO)(4)(C(4)H(10)O)(4)], features a Li(4)O(4) cube. Each Li atom in the cube is additionally coordinated by a diethyl ether mol-ecule and each O atom in the cube carries a 9-oxa-10-boraanthracene residue. The crystal studied was a non-merohedral twin [twin law (-1 0 0 / 0 0 1 / 0 1 0); the contribution of the major twin component refined to 0.553 (3)] emulating apparent tetra-gonal symmetry, whereas the actual crystal system is just ortho-rhom-bic.