Effect of Sulfonamides and Their Structurally Related Derivatives on the Activity of ι-Carbonic Anhydrase from Burkholderia territorii

Abstract

Carbonic anhydrases (CAs) are essential metalloenzymes in nature, catalyzing the carbon dioxide reversible hydration into bicarbonate and proton. In humans, breathing and many other critical physiological processes depend on this enzymatic activity. The CA superfamily function and inhibition in pathogenic bacteria has recently been the object of significant advances, being demonstrated to affect microbial survival/virulence. Targeting bacterial CAs may thus be a valid alternative to expand the pharmacological arsenal against the emergence of widespread antibiotic resistance. Here, we report an extensive study on the inhibition profile of the recently discovered ι-CA class present in some bacteria, including Burkholderia territorii, namely BteCAι, using substituted benzene-sulfonamides and clinically licensed sulfonamide-, sulfamate- and sulfamide-type drugs. The BteCAι inhibition profile showed: (i) several benzene-sulfonamides with an inhibition constant lower than 100 nM; (ii) a different behavior with respect to other α, β and γ-CAs; (iii) clinically used drugs having a micromolar affinity. This prototype study contributes to the initial recognition of compounds which efficiently and selectively inhibit a bacterial member of the ι-CA class, for which such a selective inhibition with respect to other protein isoforms present in the host is highly desired and may contribute to the development of novel antimicrobials.

Dithiocarbamates effectively inhibit the α-carbonic anhydrase from Neisseria gonorrhoeae

“…Inhibitor and enzyme solutions were preincubated together for 15 min at room temperature prior to the assay, in order to allow for the formation of the E-I complex. The inhibition constants were obtained by non-linear least-squares methods using Prism 3 and the Cheng-Prusoff equation, as reported earlier 13 , 14 , and represent the mean from at least three different determinations. The NgCA concentration in the assay system was 6.3 nM.…”

An overview on the recently discovered iota-carbonic anhydrases

“…In contrast, by adding Mn 2+ , the enzyme activity was not present or the enzyme was found to contain zinc, probably from the traces of this ion present as impurity in the used reagents 60 . The protein resulted sensitive to inhibition with substituted benzene-sulphonamides and clinically licenced sulfonamide-, sulfamate- and sulfamide-type drugs, which are among the most investigated CA inhibitors (CAIs) 61 . BteCAι inhibition profile showed several benzene-sulphonamides with an inhibition constant lower than 100 nM 61 .…”

“…The protein resulted sensitive to inhibition with substituted benzene-sulphonamides and clinically licenced sulfonamide-, sulfamate- and sulfamide-type drugs, which are among the most investigated CA inhibitors (CAIs) 61 . BteCAι inhibition profile showed several benzene-sulphonamides with an inhibition constant lower than 100 nM 61 . In addition to sulphonamides and their bioisosteres, anion and small molecules (another group of CAIs) were investigated as BteCAι inhibitors 62 .…”

Novel 1,3,5-Triazinyl Aminobenzenesulfonamides Incorporating Aminoalcohol, Aminochalcone and Aminostilbene Structural Motifs as Potent Anti-VRE Agents, and Carbonic Anhydrases I, II, VII, IX, and XII Inhibitors

“…Carbonic anhydrases (CAs, EC 4.2.1.1.) are metalloenzymes catalyzing the reversible hydration of carbon dioxide to bicarbonate anion and proton, thereby affecting related physiological processes [ 3 , 4 , 6 , 7 ]. Inhibition of bacterial CAs leads to the inhibition of growth, growth defects, and makes bacteria vulnerable to host defense mechanisms [ 4 , 8 , 9 ].…”

“…Inhibition of bacterial CAs leads to the inhibition of growth, growth defects, and makes bacteria vulnerable to host defense mechanisms [ 4 , 8 , 9 ]. Over the last few years, a number of articles describing the inhibition activity of clinically licensed or new sulfonamides against bacterial CAs presented in Vibrio cholerae [ 10 , 11 , 12 , 13 , 14 ], Mycobacterium tuberculosis [ 15 , 16 , 17 , 18 ], Burkholderia pseudomallei [ 19 ], Burkholderia territorii [ 7 , 20 ], Escherichia coli [ 21 , 22 ], and others, were published.…”