Two squalene synthase inhibitors, E5700 and ER-119884, interfere with cellular proliferation and induce ultrastructural and lipid profile alterations in a Candida tropicalis strain resistant to fluconazole, itraconazole, and amphotericin B.
Three quinuclidine-based squalene synthase (SQS) inhibitors (BPQ-OH, E5700, and ER-119884) were evaluated against five Candida tropicalis strains with different susceptibility profiles to fluconazole (FLC), itraconazole (ITC), terbinafine (TRB), and amphotericin B (AMB). Although the quinuclidine derivatives were inactive against most C. tropicalis strains tested at concentrations up to 16 μg/ml, E5700 and ER-119884 showed antifungal activity against C. tropicalis ATCC 28707, a strain resistant to FLC, ITC, and AMB, with IC(50) and IC(90) values (i.e., the minimum inhibitory concentrations of the drugs determined as the lowest drug concentrations leading to a 50 and 90% of reduction in turbidity at 492 nm, respectively, after 48 h of incubation) of 1 and 4 μg/ml, respectively. Analysis of free sterols showed that non-treated C. tropicalis ATCC 28707 cells contained only 14-methylated sterols and that treatment with E5700 or ER-119884 led to a marked reduction of squalene content and the complete disappearance of the endogenous sterols. The fatty acid and phospholipid profiles in C. tropicalis ATCC 28707 cells grown in the presence of E5700 and ER-119884 were also markedly altered, with a large increase in the content of linolenic acid (C18:3), associated with a reduction in the content of linoleic (C18:2) and oleic (C18:1) acids. Treatment of C. tropicalis ATCC 28707 with E5700 or ER-119884 IC(50) values induced several ultrastructural alterations, including a marked increase in the thickness of the cell wall and the appearance of a large number of electron-dense vacuoles. In conclusion, our results indicated that E5700 and ER-119884 inhibited the growth and altered the lipid prolife and the ultrastructure of a multiple drug-resistant C. tropicalis strain. Therefore, such compounds could act as leads for the development of new treatment options against multidrug resistant Candida species.
Laboratório de Biologia Celular de Fungos, Instituto de Biofísica Carlos Chagas Filho, Centro de Ciências da Saúde, Bloco G, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, 21949-970, Brazil.
Kelly
K
Ishida
Gonzalo
G
Visbal
Juliany Cola Fernandes
JC
Rodrigues
Julio A
JA
Urbina
Wanderley
W
de Souza
Sonia
S
Rozental
D000666:Amphotericin B / Q000494:pharmacology; D000935:Antifungal Agents / Q000737:chemistry / Q000494:pharmacology; D041022:Candida tropicalis / Q000737:chemistry / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D026141:Drug Resistance, Multiple, Fungal; D013186:Farnesyl-Diphosphate Farnesyltransferase / Q000037:antagonists & inhibitors*; D005227:Fatty Acids / Q000737:chemistry / Q000145:classification / Q000378:metabolism*; D015725:Fluconazole / Q000494:pharmacology; D008401:Gas Chromatography-Mass Spectrometry; D006651:Histocytochemistry; D020128:Inhibitory Concentration 50; D017964:Itraconazole / Q000494:pharmacology; D050356:Lipid Metabolism / Q000187:drug effects; D046529:Microscopy, Electron, Transmission; D011725:Pyridines / Q000737:chemistry / Q000494:pharmacology*; D011812:Quinuclidines / Q000737:chemistry / Q000494:pharmacology*
C489151:3-((2-benzyl-6-(3-hydroxy-4-methoxypyrrolidin-1-yl)pyridin-3-yl)ethynyl)quinuclidin-3-ol; C489152:3-((2-benzyl-6-(3-methoxypropyloxy)pyridin-3-yl)ethynyl)quinuclidin-3-ol; D000935:Antifungal Agents; D005227:Fatty Acids; D011725:Pyridines; D011812:Quinuclidines; D017964:Itraconazole; D000666:Amphotericin B; D015725:Fluconazole; D013186:Farnesyl-Diphosphate Farnesyltransferase