Phenylboronic Acids Probing Molecular Recognition against Class A and Class C β-lactamases

Abstract

Worldwide dissemination of pathogens resistant to almost all available antibiotics represent a real problem preventing efficient treatment of infectious diseases. Among antimicrobial used in therapy, β-lactam antibiotics represent 40% thus playing a crucial role in the management of infections treatment. We report a small series of phenylboronic acids derivatives (BAs) active against class A carbapenemases KPC-2 and GES-5, and class C cephalosporinases AmpC. The inhibitory profile of our BAs against class A and C was investigated by means of molecular docking, enzyme kinetics and X-ray crystallography. We were interested in the mechanism of recognition among class A and class C to direct the design of broad serine β-Lactamases (SBLs) inhibitors. Molecular modeling calculations vs GES-5 and crystallographic studies vs AmpC reasoned, respectively, the ortho derivative 2 and the meta derivative 3 binding affinity. The ability of our BAs to protect β-lactams from BLs hydrolysis was determined in biological assays conducted against clinical strains: Fractional inhibitory concentration index (FICI) tests confirmed their ability to be synergic with β-lactams thus restoring susceptibility to meropenem. Considering the obtained results and the lack of cytotoxicity, our derivatives represent validated probe for the design of SBLs inhibitors.

Cyclic and Acyclic Amine Oxide Alkyl Derivatives as Potential Adjuvants in Antimicrobial Chemotherapy against Methicillin-Resistant Staphylococcus aureus with an MDR Profile

“…The two-dimensional checkerboard microdilution assay using a 96-well microtitration plate was used to investigate the in vitro interactions between the antibiotics and detergents, as previously described by Segatore et al [ 73 , 74 ]. The microtiter plates were incubated at 37 °C for 18 h. The growth in each well was quantified spectrophotometrically at 595 nm by a microplate reader.…”

“…The data acquired from the checkerboard assay were examined by a non-parametric interpretative model based on the Loewe additivity model (Fractional Inhibitory Concentration Index, FICI), as previously described [ 74 , 75 ].…”

Class C β-Lactamases: Molecular Characteristics

“…Several bacteria from Bacteroidetes and Firmicutes (e.g. Pelosinus fermentans, Sediminibacterium salmoneum) also carry enzymes with some of these highly conserved residues and motifs: 27 G, 44 G, 58 T, 60 F, 61 E/F, 63 G, 64 SXXK, 67 K, 94 P, 115 G, 144 G, 150 YXN, 200 A, 202 G, 220 A/S, 222 G/S, 229 D, 315 K/HT/SG, 319 T, 321 GF, 337 V and 341 N. These enzymes are generally identified as serine hydrolases in databases, but with no additional bacteriological and enzymatic details that could be used to determine whether or not they should be considered as class C β-lactamases.…”

4-Amino-1,2,4-triazole-3-thione as a Promising Scaffold for the Inhibition of Serine and Metallo-β-Lactamases

“…Among metallo-BLIs (MBLIs) so far designed, bisthiazolidines, thiols, tetrazoles, sulphonamides, succinic acids, hydroxamates, and boronic acids are recurrent moieties [11,[25][26][27][28][29]. In particular, sulfur-containing molecules that are able to interfere, in the binding site, with the hydrolytic water and the Zn-ion network of interactions represent chemical entities that have been widely characterized as MBLIs.…”