title: Natural product-based phenols as novel probes for mycobacterial and fungal carbonic anhydrases.
abstract: In order to discover novel probes that may help in the investigation and control of infectious diseases through a new mechanism of action, we have evaluated a library of phenol-based natural products (NPs) for enzyme inhibition against four recently characterized pathogen β-family carbonic anhydrases (CAs). These include CAs from Mycobacterium tuberculosis, Candida albicans, and Cryptococcus neoformans as well as α-family human CA I and CA II for comparison. Many of the NPs selectively inhibited the mycobacterial and fungal β-CAs, with the two best performing compounds displaying submicromolar inhibition with a preference for fungal over human CA inhibition of more than 2 orders of magnitude. These compounds provide the first example of non-sulfonamide inhibitors that display β over α CA enzyme selectivity. Structural characterization of the library compounds in complex with human CA II revealed a novel binding mode whereby a methyl ester interacts via a water molecule with the active site zinc.
authors.affiliation: Eskitis Institute, Griffith University, Nathan, Queensland 4111, Australia.
authors.forename: Rohan A
authors.initials: RA
authors.lastname: Davis
authors.forename: Andreas
authors.initials: A
authors.lastname: Hofmann
authors.forename: Asiah
authors.initials: A
authors.lastname: Osman
authors.forename: Rebecca A
authors.initials: RA
authors.lastname: Hall
authors.forename: Fritz A
authors.initials: FA
authors.lastname: Mühlschlegel
authors.forename: Daniela
authors.initials: D
authors.lastname: Vullo
authors.forename: Alessio
authors.initials: A
authors.lastname: Innocenti
authors.forename: Claudiu T
authors.initials: CT
authors.lastname: Supuran
authors.forename: Sally-Ann
authors.initials: SA
authors.lastname: Poulsen
mesh_terms: D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry; D000935:Antifungal Agents / Q000138:chemical synthesis / Q000737:chemistry; D001688:Biological Products / Q000138:chemical synthesis / Q000737:chemistry*; D002176:Candida albicans / Q000201:enzymology*; D024401:Carbonic Anhydrase I / Q000037:antagonists & inhibitors / Q000737:chemistry; D024402:Carbonic Anhydrase II / Q000037:antagonists & inhibitors / Q000737:chemistry; D002257:Carbonic Anhydrase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry*; D002256:Carbonic Anhydrases / Q000737:chemistry*; D020134:Catalytic Domain; D003455:Cryptococcus neoformans / Q000201:enzymology*; D018360:Crystallography, X-Ray; D006801:Humans; D006860:Hydrogen Bonding; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000737:chemistry; D008958:Models, Molecular; D015394:Molecular Structure; D009169:Mycobacterium tuberculosis / Q000201:enzymology*; D010636:Phenols / Q000138:chemical synthesis / Q000737:chemistry*; D011485:Protein Binding; D054852:Small Molecule Libraries
chemical_list: D000900:Anti-Bacterial Agents; D000935:Antifungal Agents; D001688:Biological Products; D002257:Carbonic Anhydrase Inhibitors; D007527:Isoenzymes; D010636:Phenols; D054852:Small Molecule Libraries; D024401:Carbonic Anhydrase I; D024402:Carbonic Anhydrase II; D002256:Carbonic Anhydrases