Optimized synthesis of indole carboxylate metallo-beta-lactamase inhibitor EBL-3183

A new synthetic route for the preparation of the metallo-β-lactamase inhibitor pre-candidate EBL-3183 was developed and carried out on a kilogram scale. The described process starts from a commercially available indole-2-carboxylate and employs an Ellman auxiliary approach coupled with ruthenium-catalyzed stereoselective reduction for the introduction of chirality. The key spirocyclic cyclobutane motif was assembled utilizing an epoxide building block, which was conveniently obtained in diastereomerically pure form. The amount and quality of the prepared final target EBL-3183 were sufficient for the preclinical studies

Bicyclic Boronates as Potent Inhibitors of AmpC, the Class C β-Lactamase from Escherichia coli

Resistance to β-lactam antibacterials, importantly via production of β-lactamases, threatens their widespread use. Bicyclic boronates show promise as clinically useful, dual-action inhibitors of both serine- (SBL) and metallo- (MBL) β-lactamases. In combination with cefepime, the bicyclic boronate taniborbactam is in phase 3 clinical trials for treatment of complicated urinary tract infections. We report kinetic and crystallographic studies on the inhibition of AmpC, the class C β-lactamase from Escherichia coli, by bicyclic boronates, including taniborbactam, with different C-3 side chains. The combined studies reveal that an acylamino side chain is not essential for potent AmpC inhibition by active site binding bicyclic boronates. The tricyclic form of taniborbactam was observed bound to the surface of crystalline AmpC, but not at the active site, where the bicyclic form was observed. Structural comparisons reveal insights into why active site binding of a tricyclic form has been observed with the NDM-1 MBL, but not with other studied β-lactamases. Together with reported studies on the structural basis of inhibition of class A, B and D β-lactamases, our data support the proposal that bicyclic boronates are broad-spectrum β-lactamase inhibitors that work by mimicking a high energy ‘tetrahedral’ intermediate. These results suggest further SAR guided development could improve the breadth of clinically useful β-lactamase inhibition

Broad spectrum β-lactamase inhibition by a thioether substituted bicyclic boronate

β-Lactamases comprise the most widely used mode of resistance to β-lactam antibiotics. Cyclic boronates have shown promise as a new class of β-lactamase inhibitor, with pioneering potential to potently inhibit both metallo- and serine-β-lactamases. We report studies concerning a bicyclic boronate ester with a thioether rather than the more typical β-lactam antibiotic “C-6/C-7” acylamino type side chain, which is present in the penicillin/cephalosporin antibiotics. The thioether bicyclic boronate ester was tested for activity against representative serine- and metallo-β-lactamases. The results support the broad inhibition potential of bicyclic boronate based inhibitors with different side chains, including against metallo-β-lactamases from B1, B2, and B3 subclasses. Combined with previous crystallographic studies, analysis of a crystal structure of the thioether inhibitor with the clinically relevant VIM-2 metallo-β-lactamase implies that further SAR work will expand the already broad scope of β-lactamase inhibition by bicyclic boronates

Bicyclic boronates as potent inhibitors of AmpC, the class C β-lactamase from escherichia coli

Resistance to β-lactam antibacterials, importantly via production of β-lactamases, threatens their widespread use. Bicyclic boronates show promise as clinically useful, dual-action inhibitors of both serine- (SBL) and metallo- (MBL) β-lactamases. In combination with cefepime, the bicyclic boronate taniborbactam is in phase 3 clinical trials for treatment of complicated urinary tract infections. We report kinetic and crystallographic studies on the inhibition of AmpC, the class C β-lactamase from Escherichia coli, by bicyclic boronates, including taniborbactam, with different C-3 side chains. The combined studies reveal that an acylamino side chain is not essential for potent AmpC inhibition by active site binding bicyclic boronates. The tricyclic form of taniborbactam was observed bound to the surface of crystalline AmpC, but not at the active site, where the bicyclic form was observed. Structural comparisons reveal insights into why active site binding of a tricyclic form has been observed with the NDM-1 MBL, but not with other studied β-lactamases. Together with reported studies on the structural basis of inhibition of class A, B and D β-lactamases, our data support the proposal that bicyclic boronates are broad-spectrum β-lactamase inhibitors that work by mimicking a high energy ‘tetrahedral’ intermediate. These results suggest further SAR guided development could improve the breadth of clinically useful β-lactamase inhibition

Seeking the lowest phase transition temperature in a cellulosic system for textile applications

Smart or intelligent polymeric materials respond to small changes in their environment with a considerable change in their physicochemical properties. Environmentally responsive hydrogels have the capability to turn from solution to gel, when a specific stimulus like temperature, pH, chemicals, ultrasounds, light, electric fields and mechanical stress, is applied. Cellulose esters thermoreversible hydrogels, like HPMC, MC and NaCMC, are very appealing once they are naturally derived from cellulose, which is the most abundant naturally occurring biopolymer on earth. Allied to this advantage it is also associated the non-toxicity, biocompatibility, biodegradability and eco-friendly properties. The transition temperature of the abovementioned cellulose derivatives is medium/high (82.5, 67.5 and 47.5 degrees C) that is considerable elevated for most biochemical and textile applications. Therefore, within this research it is reported a systematic study to depress the gelation temperature of the cellulosic NaCMC. Several factors may influence sol-gel transition temperature of this cellulosic but herein the focus stood on the influence of polymer concentration, of admixing inorganic salts (NaCl and enriched salt solutions), polyols (glycerol) and polyols salts (Na/CaGlyPhos) and lastly the interaction with polyelectrolytes (CH-NaGlyPhos). The aforementioned modifications were afterward registered by UV-Vis spectroscopy. For the developed stimuli sensitive hydrogels it is envisioned the application on the textile materials, more specifically in the delivery of active species (e.g., scents, moisturizers, antiperspirants)/perspiration absorption, through textile apparel. The system will be triggered by human body temperature and thus a thermogelation temperature of 28-35 degrees C (skin-cloths microclimate temperature) is compulsory.- The authors thankfully acknowledge the funding from the Chemistry Centre at Minho University (Pest-C/QUI/UI0686/2013, UID/QUI/0686/2016), and the Portuguese Foundation for Science and Technology (FCT) and the Human Capital Operational Program (POCH), for the Post-Doc grant assigned to Sandra Cerqueira Barros (SFRH/BPD/85399/2012). The researchers involved in this work are also grateful to the Company Devan-Micropolis, S.A., for the supply of the biopolymers hydroxypropylmethyl cellulose (HPMC), methyl cellulose (MC) and sodium carboxymethyl cellulose (NaCMC), applied within this research work