Bisthiazolidine (BTZ) inhibitors of NDM-1: the importance of the thiol substituent

ROSSI, A.; GONZALEZ, M.M.; MAHLER, G. ; VILA, A.J.*; CASTILLO, V.; SPENCER, J.; LLARRULL, L.I.; BONOMO, R.A.; SAIZ, C.; MOJICA, M.F.; VILLAMIL, V.; CASTELLANO, L.

Boston

Congreso; 2016 ASM Microbe; 2016

American Society for Microbiology

Background: Carbapenems are recognized as ?last-resort? beta-lactam drugs. However, the appearance of highly resistant bacteria producing metallo-beta-lactamases (MBLs), such NDM-1 (New Delhi Metallo-beta-lactamase-1), challenge the therapeutic primacy of carbapenems in the clinical setting. NDM-1 and other B1 MBLs are able to hydrolyze almost all beta-lactam classes and are not inhibited by available serine-beta-lactamase inhibitors. Clinically useful MBL inhibitors have not yet been introduced into the clinic. Recently, the synthesis and biological characterization of the first series of BTZ heterocycles against the MBLs from B1 subclass (NDM-1, VIM-2 and VIM-24) was reported. From the crystal structures between the MBLs with BTZs, we found that the thiol moiety present in the BTZ scaffold is intercalated between both Zn(II) ions and forms a stable ternary complex. Our goal is to explore the importance of the thiol interaction with NDM-1 in a novel series of derivatives. Methods: BTZ derivatives were synthesized wherein the thiol group was replaced with fluoroalkyl, carboxylate, sulfonic acid, tetrazole groups or methylated as a thiomethyl derivative. MBLs were purified to homogeneity. Inhibition constants were determined by following imipenem hydrolysis at 300 nm absorbance The inhibition constants were determined by data fitting to the Competitive Inhibition Model.Results: The inhibition assays against NDM-1 revealed that in all cases the substitution of the thiol moiety is essential for the inhibitory activity, highlighting the importance of thiol groups as the main driving force for the inhibition observed in MBLs. Instead, insertion of substituents in the bridging position did not affect the inhibition constants in the low micromolar range observed for the first series of BTZs.Conclusions: We report the essential nature of thiol groups in BTZs for MBL. These compounds represent a versatile and promising scaffold for the investigation and development of molecules with a diverse set of moieties capable of inhibiting MBLs.