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91.
Maria-Agustina Rossi Veronica Martinez Philip Hinchliffe Maria F. Mojica Valerie Castillo Diego M. Moreno Ryan Smith Brad Spellberg George L. Drusano Claudia Banchio Robert A. Bonomo James Spencer Alejandro J. Vila Graciela Mahler 《Chemical science》2021,12(8):2898
Infections caused by multidrug resistant (MDR) bacteria are a major public health threat. Carbapenems are among the most potent antimicrobial agents that are commercially available to treat MDR bacteria. Bacterial production of carbapenem-hydrolysing metallo-β-lactamases (MBLs) challenges their safety and efficacy, with subclass B1 MBLs hydrolysing almost all β-lactam antibiotics. MBL inhibitors would fulfil an urgent clinical need by prolonging the lifetime of these life-saving drugs. Here we report the synthesis and activity of a series of 2-mercaptomethyl-thiazolidines (MMTZs), designed to replicate MBL interactions with reaction intermediates or hydrolysis products. MMTZs are potent competitive inhibitors of B1 MBLs in vitro (e.g., Ki = 0.44 μM vs. NDM-1). Crystal structures of MMTZ complexes reveal similar binding patterns to the most clinically important B1 MBLs (NDM-1, VIM-2 and IMP-1), contrasting with previously studied thiol-based MBL inhibitors, such as bisthiazolidines (BTZs) or captopril stereoisomers, which exhibit lower, more variable potencies and multiple binding modes. MMTZ binding involves thiol coordination to the Zn(ii) site and extensive hydrophobic interactions, burying the inhibitor more deeply within the active site than d/l-captopril. Unexpectedly, MMTZ binding features a thioether–π interaction with a conserved active-site aromatic residue, consistent with their equipotent inhibition and similar binding to multiple MBLs. MMTZs penetrate multiple Enterobacterales, inhibit NDM-1 in situ, and restore carbapenem potency against clinical isolates expressing B1 MBLs. Based on their inhibitory profile and lack of eukaryotic cell toxicity, MMTZs represent a promising scaffold for MBL inhibitor development. These results also suggest sulphur–π interactions can be exploited for general ligand design in medicinal chemistry.Metallo-β-lactamases (MBLs) are major culprits of resistance to carbapenems in bacteria. A series of thiazolidines are potent MBL inhibitors, restoring the activity of carbapenems. Metal binding and sulphur–π interactions are key to inhibition. 相似文献
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P-Nitrosophosphates, such as 9, react as N-O heterodienophiles with 1,3-dienes to form highly functionalized cycloadducts that can be directly transformed into allylic phosphoramidates. The in situ periodate oxidation of the unstable N-hydroxyphosphoramidate precursors provides an efficient preparation of these new reactive intermediates. P-Nitrosophosphate (9) regioselectively reacts with 1-methoxy-1,3-butadiene to provide cycloadduct 16. P-Nitrosophosphate (9) also reacts with 9,10-dimethylanthracene to give cycloadduct 17, which undergoes retro Diels-Alder dissociation to re-form 9. In the absence of a 1,3-diene, the decomposition of 17 produces nitrous oxide, evidence for nitroxyl, the one-electron-reduced form of nitric oxide. An asymmetric P-nitrosophosphate reacted with 1,3-cyclohexadiene to form a mixture of diastereomeric cycloadducts (19 and 20) in a 1.6:1 ratio. These results identify P-nitrosophosphates as new species that react similarly to acyl nitroso compounds, making them useful synthetic intermediates and potential nitroxyl delivery agents. 相似文献
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Schumm BA Koetke DS Adolphsen CE Alexander JP Averill D Barish BC Barklow T Barnett BA Blockus D Boyarski A Brabson B Breakstone A Bulos F Burchat PR Burke DL Cence RJ Chapman J Chmeissani M Cords D Coupal DP Dauncey P DeStaebler HC Dorfan JM Drell PS Drewer DC Durrett D Elia R Feldman GJ Field RC Ford WT Fordham C Frey R Fujino D Gan KK Gero E Gidal G Glanzman T Goldhaber G Gomez Cadenas JJ Gratta G Hanson G Harr R Harral B Harris FA Hayes K Hearty C Heusch CA Hildreth MD Himel T Hinshaw DA 《Physical review D: Particles and fields》1992,46(1):453-456
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Irreducible covariant tensor modules for the Lie supergroups GL(m/n) and the Lie superalgebras gl(m/n) and sl(m/n) are obtained through the use of Young tableaux techniques. The starting point is the graded permutation action, first introduced by Dondi and Jarvis, on V
l
. The isomorphism between this group of actions and the symmetric group S
l enables the graded generalization of the Young symmetrizers, and hence of the column relations and Garnir relations, to be made. Consequently, corresponding to each partition of l an irreducible GL(m/n) module may be obtained as a submodule of V
l
. A basis for the module labeled by the partition is provided by GL(m/n)–standard tableaux of shape defined by Berele and Regev. The reduction of an arbitrary tableau to standard form is accomplished through the use of graded column relations and graded Garnir relations. The standardization procedure is algorithmic and allows matrix representations of the Lie superalgebras gl(m/n) and sl(m/n) to be constructed explicitly over the field of rational numbers. All the various steps of the standardization algorithm are exemplified, as well as the explicit construction of matrices representing particular elements of gl(m/n) and sl(m/n). 相似文献