Bacterial Ectonucleotidases: Underexplored Antibacterial Drug Targets

The bacterial ecto-5′-nucleotidases (5′-NTs) are metalloenzymes that hydrolyze 5′-nucleoside-monophosphates (NMPs) to generate nucleosides and phosphate. These metallophosphoesterases are found in the periplasmic space and cytoplasm or are connected to the bacterial outer membrane. Membrane-bound and periplasmic 5′-NTs break down extracellular nucleotides for microbe feeding requirements, whereas cytosolic 5′-NTs control the bacterial ribo- and deoxyribonucleoside monophosphates and nucleotides levels. Both membrane-associated and periplasmic 5′-NTs have been linked to enhanced microbial virulence and pathogenicity for various pathogenic microorganisms, including Staphylococcus aureus, Vibrio cholerae, Streptococcus agalactiae, Pseudomonas aeruginosa, and Legionella pneumophila. Although these enzymes are considered as potential targets for developing inhibitors with pharmacological action as antibacterials, few drug design studies have been described in the literature. At the moment, only protein-based products, natural polyphenolic compounds, and 1-amino-4-ar(alk)ylamino-2-sulfoanthraquinones with low-micromolar IC50 values were described as bacterial 5′-NT inhibitors. Thus, this chapter may serve as a warning for the scientific community to find inhibitors of bacterial 5-NTs, which may represent a potential solution to the troublesome issue of antibiotic resistance to presently used anti-infective agents.