Bioorganic & Medicinal Chemistry Letters
Activity of caffeic acid derivatives against Candida albicans biofilm
Daniela De Vita a, , Laura Friggeri a, , Felicia Diodata D’Auria c, Fabiana Pandolfi a, Francesco Piccoli a,
a,
b
Simona Panella c, Anna Teresa Palamara c, Giovanna Simonetti c, , Luigi Scipione , Roberto Di Santo ,
⇑
⇑
Roberta Costi b, Silvano Tortorella a
a Department of ‘Chimica e Tecnologie del Farmaco’, Sapienza University of Rome, Piazzale Aldo Moro, 5, 00185 Rome, Italy
b ‘Istituto Pasteur-Fondazione Cenci Bolognetti’, Department of ‘Chimica e Tecnologie del Farmaco’, Sapienza University of Rome, Piazzale Aldo Moro, 5, 00185 Rome, Italy
c Department of ‘Sanità Pubblica e Malattie Infettive’, Sapienza University of Rome, Piazzale Aldo Moro, 5, 00185 Rome, Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
The aim of this study was to evaluate the caffeic acid (1) and ester derivatives (2–10) against Candida albi-
cans biofilm and to investigate whether these compounds are able to inhibit the biofilm formation or
destroy pre-formed biofilm.
Received 5 December 2013
Revised 30 January 2014
Accepted 3 February 2014
Available online 13 February 2014
Caffeic acid ester 7, cinnamic acid ester 8 and 3,4-dihydroxybenzoic acid ester 10 are more active than
fluconazole, used as reference drug, both on biofilm in formation with MIC50 values of 32, 32 and 16
mL, respectively, and in the early stage of biofilm formation (4 h) with MIC50 values of 64, 32 and 64
l
l
g/
g/
Keywords:
Candida albicans biofilm
Caffeic acid
Anti-biofilm agents
Biofilm formation
mL, respectively. These esters result also more active than fluconazole on mature biofilm (24 h), espe-
cially 8 and 10 with MIC50 values of 64 g/mL.
l
Ó 2014 Elsevier Ltd. All rights reserved.
Candida species are opportunistic pathogens that can cause a
wide variety of infections and they are the main agents responsible
for nosocomial fungal infections. Candida spp. can form readily bio-
film on indwelling medical devices and mucosal tissues. This bio-
film turns out to be an infectious reservoir difficult to eradicate,
and it causes device-associated infections with high mortality.1,2
The most prevalent fungal biofilm-forming pathogen is Candida
albicans, which cause both superficial and systemic infections. C.
albicans is able to colonize and form biofilms on devices such as
shunts, stents, endotracheal tubes and various types of catheters.3
Indeed, it has been reported that infections caused by biofilm-
forming C. albicans were significantly correlated with increased
mortality.4
The early stage of C. albicans biofilm formation is characterized
by the adhesion of single cells to the substratum, that was followed
by the formation of an intricate network of hyphae and the begin-
ning of a dense structure. Changes in the transcriptome begin
within 30 min of contact with the substrate. Some of these changes
are initiated early and maintained throughout the process; other
changes are typical of the earliest stages of biofilm formation.5
Among the phenotypic alterations displayed by cells in biofilms,
the most relevant from the clinical point of view is the increased
resistance to antifungal treatments.6,7 Compared to their plank-
tonic counterparts, biofilm cells exhibit up to a 1000-fold increased
resistance.
C. albicans biofilms have been reported to be resistant to a
variety of clinical antifungal agents, including fluconazole,8
a
well-tolerated antifungal drug, commonly used in the treatment
of candidiasis. Among the available antifungal agents, only
echinocandins and amphotericin B lipid formulations have shown
consistent activity against Candida biofilms. Unfortunately,
amphotericin B can cause severe nephrotoxicity to the host and
echinocandins are highly expensive to be used routinely.9 There-
fore, in this scenario, there is an urgent need for low-cost
compounds with a better efficacy and low side effects.
Several molecules were reported in literature to inhibit or
to prevent the C. albicans biofilm formation. Many of these
compounds are characterized by phenylethenyl moieties, such as
4-hydroxycordoin and methyl cinnamate;10,11 among these
molecules, caffeic acid phenethyl ester (CAPE) is able to inhibit
both Candida filamentation and biofilm formation (Chart 1).12
We have decided to test caffeic acid (1) and the ester derivatives
(2–10) against C. albicans planktonic and biofilm cells, in order to
evaluate the effects on anti-biofilm activity of structural modifica-
tion on the alcoholic and carboxylic moieties. The assessment of
anti-biofilm activity of these compounds may allow to understand
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Corresponding authors. Tel.: +39 0649970115; fax: +39 064468625 (G.S.); tel.:
+39 0649913737; fax: +39 0649913133 (L.S.).
These authors contributed equally to this work.
0960-894X/Ó 2014 Elsevier Ltd. All rights reserved.