Bicyclic Boronate VNRX-5133 Inhibits Metallo- and Serine-β-Lactamases

The bicyclic boronate VNRX-5133 (taniborbactam) is a new type of β-lactamase inhibitor in clinical development. We report that VNRX-5133 inhibits serine-β-lactamases (SBLs) and some clinically important metallo-β-lactamases (MBLs), including NDM-1 and VIM-1/2. VNRX-5133 activity against IMP-1 and tested B2/B3 MBLs was lower/not observed. Crystallography reveals how VNRX-5133 binds to the class D SBL OXA-10 and MBL NDM-1. The crystallographic results highlight the ability of bicyclic boronates to inhibit SBLs and MBLs via binding of a tetrahedral (sp3) boron species. The structures imply conserved binding of the bicyclic core with SBLs/MBLs. With NDM-1, by crystallography, we observed an unanticipated VNRX-5133 binding mode involving cyclization of its acylamino oxygen onto the boron of the bicyclic core. Different side-chain binding modes for bicyclic boronates for SBLs and MBLs imply scope for side-chain optimization. The results further support the "high-energy-intermediate" analogue approach for broad-spectrum β-lactamase inhibitor development and highlight the ability of boron inhibitors to interchange between different hybridization states/binding modes

High-throughput crystallography reveals boron-containing inhibitors of a Penicillin-binding protein with di- and tricovalent binding modes

The effectiveness of β-lactam antibiotics is increasingly compromised by β-lactamases. Boron-containing inhibitors are potent serine-β-lactamase inhibitors, but the interactions of boron-based compounds with the penicillin-binding protein (PBP) β-lactam targets have not been extensively studied. We used high-throughput X-ray crystallography to explore reactions of a boron-containing fragment set with the PBP3 (PaPBP3). Multiple crystal structures reveal that boronic acids react with PBPs to give tricovalently linked complexes bonded to Ser294, Ser349, and Lys484 of PaPBP3; benzoxaboroles react with PaPBP3 via reaction with two nucleophilic serines (Ser294 and Ser349) to give dicovalently linked complexes; and vaborbactam reacts to give a monocovalently linked complex. Modifications of the benzoxaborole scaffold resulted in a moderately potent inhibition of PaPBP3, though no antibacterial activity was observed. Overall, the results further evidence the potential for the development of new classes of boron-based antibiotics, which are not compromised by β-lactamase-driven resistance

Psychological contract in the selected institute of public administration: comparison of logistic department and other departments

V diplomskem delu obravnavamo poznavanje psihološke pogodbe in motiviranost zaposlenih v izbranem zavodu javne uprave. S pomočjo anketnega vprašalnika bomo ugotovili, katere psihološke pogodbe so zastopane med zaposlenimi in katera prevladuje. Diplomsko delo je sestavljeno iz teoretičnega in empiričnega dela. Teoretični del sestoji iz psihološke pogodbe in motivacije. Za psihološko pogodbo smo navedli nekaj definicij različnih avtorjev, opisali posamezne oblike psiholoških pogodb in z navedbo bistvenih sestavin psihološke pogodbe poudarili pomembnost te. Opredelili smo tudi motivacijo zaposlenih v povezavi s psihološkimi pogodbami. Podali smo nekaj razlag različnih avtorjev, opisali nekatere motivacijske teorije in navedli bistvene motivatorje in demotivatorje za posamezno psihološko pogodbo. Opisali smo tudi pojav demotivacije. V empiričnem delu smo predstavili metode dela in s pomočjo anketnega vprašalnika za psihološko pogodbo avtorice Renate Mihalič in motivacije avtorja Vida Pogačnika, pridobili rezultate o prevladujoči psihološki pogodbi in stopnji motivacije zaposlenih v izbranem zavodu. Opravili smo tudi primerjavo med zaposlenimi v logističnem oddelku in v drugih oddelkih ter statistično pomembno povezanost med psihološkimi pogodbami in motivacijo. Preverili smo zadane hipoteze in v zaključku strnili ugotovitve raziskave.In the diploma thesis, we discuss the acquaintance with the psychological contract and the motivation of employees in the selected public administration institution. Furthermore, by utilizing a survey questionnaire, we explored which psychological contracts were represented among employees and which one prevailed. The thesis is comprised of a theoretical and an empirical part. The theoretical part consists of the psychological contract and motivation. For the psychological contract, we presented some definitions from different authors, described individual forms of psychological contracts, and, by stating the essential components of the psychological contract, we stressed its significance. We also defined employee motivation in connection with psychological contracts. We gave some explanations from different authors, described some motivational theories and listed the essential motivators and demotivators for each psychological contract. We also described the phenomenon of demotivation. In the empirical part, we presented work methods, and with the help of a survey questionnaire for the psychological contract authored by Renata Mihalič and motivation authored by Vid Pogačnik, we obtained results about the prevailing psychological contract and the level of motivation of the employees in the selected institution. We also performed a comparison between employees in the logistics department and other departments and showed a statistically significant connection between psychological contracts and motivation. In conclusion, the hypotheses were tested, and the research findings were summarised

Conjugates of monocyclic β-lactams and siderophore mimetics

Introduction: β-Lactams, which include monobactams, remain the most important class of antibiotics worldwide. Aztreonam, the only monobactam in clinical use, has remarkable activity against many Gram-negative bacteria, but limited activity against some of the most problematic multidrug-resistant (MDR) pathogens, such as MDR Pseudomonas aeruginosa and Acinetobacter baumannii co-expressing extended-spectrum- and metallo-β-lactamases, which can inactivate aztreonam by hydrolysis. Areas covered: Structurally novel siderophore-conjugated aztreonam derivatives with improved antibacterial properties against several high-priority pathogens are claimed. This invention reports that sidechain extension of aztreonam is toleratedthe coupling of its aminothiazoloxime carboxylic acid part with a siderophore mimetic significantly improved the antibacterial activity against several problematic strains, including MDR A. baumannii isolates with carbapenemase/cephalosporinase activity. Expert Opinion: Finding new strategies to tackle bacterial resistance to β-lactam antibiotics is critical. Considering that β lactams are validated and safe drugs, this research may stimulate the field to develop new ideas in the arena of antimicrobial drug discovery, particularly with respect to siderophore mimetics

Structural basis of prolyl hydroxylase domain inhibition by Molidustat

Human prolyl-hydroxylases (PHDs) are hypoxia-sensing 2-oxoglutarate (2OG) oxygenases, catalysis by which suppresses the transcription of hypoxia-inducible factor target genes. PHD inhibition enables the treatment of anaemia/ischaemia-related disease. The PHD inhibitor Molidustat is approved for the treatment of renal anaemia; it differs from other approved/late-stage PHD inhibitors in lacking a glycinamide side chain. The first reported crystal structures of Molidustat and IOX4 (a brain-penetrating derivative) complexed with PHD2 reveal how their contiguous triazole, pyrazolone and pyrimidine/pyridine rings bind at the active site. The inhibitors bind to the active-site metal in a bidentate manner through their pyrazolone and pyrimidine nitrogens, with the triazole π-π-stacking with Tyr303 in the 2OG binding pocket. Comparison of the new structures with other PHD inhibitor complexes reveals differences in the conformations of Tyr303, Tyr310, and a mobile loop linking β2-β3, which are involved in dynamic substrate binding/product release