Infections caused by pathogens resistant to the available antimicrobial treatments represent nowadays a threat to global public health. Recently, it has been demonstrated that carbonic anhydrases (CAs) are essential for the growth of many pathogens and their inhibition leads to growth defects. Principal drawbacks in using CA inhibitors (CAIs) as antimicrobial agents are the side effects due to the lack of selectivity toward human CA isoforms. Herein we report a new class of CAIs, which preferentially interacts with microbial CA active sites over the human ones. The mechanism of action of these inhibitors was investigated against an important fungal pathogen, Cryptococcus neoformans, revealing that they are also able to inhibit CA in microbial cells growing in vitro. At our best knowledge, this is the first report on newly designed synthetic compounds selectively targeting β-CAs and provides a proof of concept of microbial CAs suitability as an antimicrobial drug target.

Discovering a new class of antifungal agents that selectively inhibits microbial carbonic anhydrases / Annunziato, Giannamaria; Giovati, Laura; Andrea, Angeli; Pavone, Marialaura; Sonia Del Prete, ; Pieroni, Marco; Clemente, Capasso; Bruno, Agostino; Conti, Stefania; Magliani, Valter; Supuran, Claudiu T.; Costantino, Gabriele. - In: JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY. - ISSN 1475-6366. - 33:1(2018), pp. 1537-1544. [10.1080/14756366.2018.1516652]

Discovering a new class of antifungal agents that selectively inhibits microbial carbonic anhydrases

Giannamaria Annunziato
;
Laura Giovati;PAVONE, MARIALAURA;Marco Pieroni;Agostino Bruno;Stefania Conti;Walter Magliani;Gabriele Costantino
2018

Abstract

Infections caused by pathogens resistant to the available antimicrobial treatments represent nowadays a threat to global public health. Recently, it has been demonstrated that carbonic anhydrases (CAs) are essential for the growth of many pathogens and their inhibition leads to growth defects. Principal drawbacks in using CA inhibitors (CAIs) as antimicrobial agents are the side effects due to the lack of selectivity toward human CA isoforms. Herein we report a new class of CAIs, which preferentially interacts with microbial CA active sites over the human ones. The mechanism of action of these inhibitors was investigated against an important fungal pathogen, Cryptococcus neoformans, revealing that they are also able to inhibit CA in microbial cells growing in vitro. At our best knowledge, this is the first report on newly designed synthetic compounds selectively targeting β-CAs and provides a proof of concept of microbial CAs suitability as an antimicrobial drug target.
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11381/2851044
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