Abstract
To fight the increasingly worrying bacterial resistance to antibiotics, the discovery and development of new therapeutics is urgently needed. Here, we report on a new series of 1,2,4-triazole-3-thione compounds as inhibitors of metallo-β-lactamases (MBLs), which represent major resistance determinants to β-lactams, and especially carbapenems, in Gram-negative bacteria. These molecules are stable analogs of 4-amino-1,2,4-triazole-derived Schiff bases, where the hydrazone-like bond has been reduced (hydrazine series) or the 4-amino group has been acylated (hydrazide series); the synthesis and physicochemical properties thereof are described. The inhibitory potency was determined on the most clinically relevant acquired MBLs (IMP-, VIM-, and NDM-types subclass B1 MBLs). When compared with the previously reported hydrazone series, hydrazine but not hydrazide analogs showed similarly potent inhibitory activity on VIM-type enzymes, especially VIM-2 and VIM-4, with Ki values in the micromolar to submicromolar range. One of these showed broad-spectrum inhibition as it also significantly inhibited VIM-1 and NDM-1. Restoration of β-lactam activity in microbiological assays was observed for one selected compound. Finally, the binding to the VIM-2 active site was evaluated by isothermal titration calorimetry and a modeling study explored the effect of the linker structure on the mode of binding with this MBL.
Highlights
In the early 1900s, bacterial infections represented one of the most significant causes of death in the world
Due to the natural selective pressure exerted by exogenous agents, bacteria developed a plethora of resistance mechanisms to allow their survival in selective conditions and, significantly compromise the therapeutic efficacy of antibiotics [2,3]
The reaction rate was measured as the variation of absorbance observed upon substrate hydrolysis in a UV-Vis spectrophotometer or microplate reader at a wavelength of 300 nm, 260 nm, or 482 nm and in the presence of a purified MBL enzyme
Summary
In the early 1900s, bacterial infections represented one of the most significant causes of death in the world This plague has been circumvented by the development of several classes of antibiotics, including the β-lactams, which show optimal efficacy and selectivity. Β-lactam antibiotics include four sub-families: penicillins, cephalosporins, monobactams, and carbapenems The latter were developed for the treatment of infections caused by multidrug-resistant Gram-negative opportunistic pathogens, and are exclusively used in the hospital setting, commonly as a last resort therapeutic option. Shortly after the introduction of carbapenems into clinical practice, acquired metallo-β-lactamases (MBLs), belonging to Ambler’s class B, emerged in Gram-negative opportunistic pathogens [13,14] They are characterized by the presence of one or two zinc atoms in the active site. PPrreevviioouuss wwoorrkk oonn hhyyddrraazzoonnee--lliikkee ccoommppoouunnddss aanndd ddeessiiggnn ooff nneeww ssttaabbllee sseerriieess ((KKii vvaalluueess aarree ggiivveenn ffoorr SScchhiiffff bbaassee JJMMVV44339900 ((sseeee tthhee uunnppuubblliisshheeddwwoorrkkiinn[[3377]]))))
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