Title:Inhibition of Bacterial Carbonic Anhydrases as a Novel Approach to Escape Drug Resistance
Volume: 17
Issue: 11
Author(s): Clemente Capasso and Claudiu T. Supuran
Affiliation:
Keywords:
Carbonic anhydrase, Hydratase activity, Metalloenzymes, CA inhibitors, Pathogens, Selective inhibition, Antibacterial,
Antiinfective, Sulfonamide, Anions, Inhibitor selectivity, Drug-design.
Abstract: Background: Clinically used antibiotics act through one of these four mechanisms: cell wall
biosynthesis inhibition, inhibition of protein biosynthesis, interference with DNA and RNA synthesis
and the folate pathway.
Objective: The metalloenzymes carbonic anhydrases (CAs, EC 4.2.1.1) widespread in microorganisms
and present as three genetically distinct families may be considered for the design of antiinfective agents
with a different mechanism of action compared to the clinically used antibiotics. CAs are crucial for the
life cycle of the pathogen, interfering with pH regulation and biosynthetic processes in which CO2 or
bicarbonate are substrates. CA inhibition was shown to lead to debilitation or growth defects of several
pathogenic bacteria.
Method: CAs catalyzes the interconversion between carbon dioxide to bicarbonate, leading to the formation
of protons, and thus affecting pH homeostasis. Several classes of CA inhibitors (CAIs) are
known to date, among which the metal complexing anions, the unsubstituted sulfonamides, the dithiocarbamates,
etc., which bind to the Zn(II) ion of the enzyme either by substituting the non-protein zinc
ligand or add to the metal coordination sphere.
Results: Effective inhibitors for many bacterial CAs belonging to the α-, β-, and γ-CA classes were detected,
some of which inhibited bacterial growth in vivo. Few of the inhibitors investigated so far were
also selective for the bacterial over the human CA isoforms, which may pose problems for their wide
clinical applications.
Conclusion: Structure-based drug design campaigns might lead to the achievement of the desired selectivity/
potency for preferentially inhibiting bacterial but not the host CAs.
