TY - JOUR
T1 - In vitro characterization, ADME analysis, histological and toxicological evaluation of BM1, a macrocyclic amidinourea active against azole-resistant Candida strains
AU - Torelli, Riccardo
AU - Martini, Cecilia
AU - Sanguinetti, Maurizio
AU - Bugli, Francesca
PY - 2020
Y1 - 2020
N2 - BACKGROUND: Among the opportunistic fungi, Candida species represent one of the most common causes of nosocomial bloodstream infections. The large use of antifungal agents, most of them launched on the market more than twenty years ago, led to the selection of drug-resistant or even multidrug-resistant fungi. In the last years, we described a novel class of antifungal macrocyclic compounds bearing an amidinourea moiety, highly active against various azole-resistant Candida strains. OBJECTIVE: In this study, one representative of this family, compound BM1, has been investigated on its in vitro activity against various Candida species, including C. auris isolates, its interaction with the ABC transporter CDR6 and its in vivo distribution and safety. METHODS: In vitro assays (CYP inhibition, microsomal stability, permeability, spot assays) have been used to collect chemical and biological data; animal models (rat) paired with LC-MS analysis have been exploited to evaluate in vivo toxicology, pharmacokinetics, and distribution. RESULTS: Our research highlights the low in vivo toxicity profile of BM1, its affinity for the renal system in rats and its good absorption, distribution, metabolism, and excretion (ADME) features. Our compound preserves a potent activity also against azole-resistant fungal strains, including C. auris isolates and CDR6-overexpressing strains. CONCLUSIONS: We confirmed low MICs against several Candida species, including preliminary data versus C. auris. The good ADME and biochemical characteristics make BM1 suitable and safe for daily administration and particularly indicated to treat renal infections. These data make BM1 and its derivatives a novel promising antifungal class.
AB - BACKGROUND: Among the opportunistic fungi, Candida species represent one of the most common causes of nosocomial bloodstream infections. The large use of antifungal agents, most of them launched on the market more than twenty years ago, led to the selection of drug-resistant or even multidrug-resistant fungi. In the last years, we described a novel class of antifungal macrocyclic compounds bearing an amidinourea moiety, highly active against various azole-resistant Candida strains. OBJECTIVE: In this study, one representative of this family, compound BM1, has been investigated on its in vitro activity against various Candida species, including C. auris isolates, its interaction with the ABC transporter CDR6 and its in vivo distribution and safety. METHODS: In vitro assays (CYP inhibition, microsomal stability, permeability, spot assays) have been used to collect chemical and biological data; animal models (rat) paired with LC-MS analysis have been exploited to evaluate in vivo toxicology, pharmacokinetics, and distribution. RESULTS: Our research highlights the low in vivo toxicity profile of BM1, its affinity for the renal system in rats and its good absorption, distribution, metabolism, and excretion (ADME) features. Our compound preserves a potent activity also against azole-resistant fungal strains, including C. auris isolates and CDR6-overexpressing strains. CONCLUSIONS: We confirmed low MICs against several Candida species, including preliminary data versus C. auris. The good ADME and biochemical characteristics make BM1 suitable and safe for daily administration and particularly indicated to treat renal infections. These data make BM1 and its derivatives a novel promising antifungal class.
KW - ADMET
KW - Antifungal
KW - Candida
KW - In vitro
KW - In vivo
KW - Pharmacokinetics
KW - ADMET
KW - Antifungal
KW - Candida
KW - In vitro
KW - In vivo
KW - Pharmacokinetics
UR - http://hdl.handle.net/10807/144913
U2 - 10.1016/j.ijantimicag.2019.105865
DO - 10.1016/j.ijantimicag.2019.105865
M3 - Article
SN - 0924-8579
VL - 55
SP - N/A-N/A
JO - International Journal of Antimicrobial Agents
JF - International Journal of Antimicrobial Agents
ER -