title: A novel antifungal is active against Candida albicans biofilms and inhibits mutagenic acetaldehyde production in vitro.
abstract: The ability of C. albicans to form biofilms is a major virulence factor and a challenge for management. This is evident in biofilm-associated chronic oral-oesophageal candidosis, which has been shown to be potentially carcinogenic in vivo. We have previously shown that most Candida spp. can produce significant levels of mutagenic acetaldehyde (ACH). ACH is also an important mediator of candidal biofilm formation. We have also reported that D,L-2-hydroxyisocaproic acid (HICA) significantly inhibits planktonic growth of C. albicans. The aim of the present study was to investigate the effect of HICA on C. albicans biofilm formation and ACH production in vitro. Inhibition of biofilm formation by HICA, analogous control compounds or caspofungin was measured using XTT to measure biofilm metabolic activity and PicoGreen as a marker of biomass. Biofilms were visualised by scanning electron microscopy (SEM). ACH levels were measured by gas chromatography. Transcriptional changes in the genes involved in ACH metabolism were measured using RT-qPCR. The mean metabolic activity and biomass of all pre-grown (4, 24, 48 h) biofilms were significantly reduced after exposure to HICA (p<0.05) with the largest reductions seen at acidic pH. Caspofungin was mainly active against biofilms pre-grown for 4 h at neutral pH. Mutagenic levels (>40 μM) of ACH were detected in 24 and 48 h biofilms at both pHs. Interestingly, no ACH production was detected from D-glucose in the presence of HICA at acidic pH (p<0.05). Expression of genes responsible for ACH catabolism was up-regulated by HICA but down-regulated by caspofungin. SEM showed aberrant hyphae and collapsed hyphal structures during incubation with HICA at acidic pH. We conclude that HICA has potential as an antifungal agent with ability to inhibit C. albicans cell growth and biofilm formation. HICA also significantly reduces the mutagenic potential of C. albicans biofilms, which may be important when treating bacterial-fungal biofilm infections.
authors.forename: Mikko T
authors.initials: MT
authors.lastname: Nieminen
authors.forename: Lily
authors.initials: L
authors.lastname: Novak-Frazer
authors.forename: Wilma
authors.initials: W
authors.lastname: Rautemaa
authors.forename: Ranjith
authors.initials: R
authors.lastname: Rajendran
authors.forename: Timo
authors.initials: T
authors.lastname: Sorsa
authors.forename: Gordon
authors.initials: G
authors.lastname: Ramage
authors.forename: Paul
authors.initials: P
authors.lastname: Bowyer
authors.forename: Riina
authors.initials: R
authors.lastname: Rautemaa
mesh_terms: D000079:Acetaldehyde / Q000493:pharmacokinetics / Q000633:toxicity; D000935:Antifungal Agents / Q000494:pharmacology*; D018441:Biofilms / Q000187:drug effects*; D002176:Candida albicans / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D002208:Caproates / Q000494:pharmacology*; D000077336:Caspofungin; D054714:Echinocandins / Q000494:pharmacology; D005656:Fungal Proteins / Q000235:genetics; D015966:Gene Expression Regulation, Fungal / Q000187:drug effects; D055666:Lipopeptides; D008855:Microscopy, Electron, Scanning
chemical_list: D000935:Antifungal Agents; D002208:Caproates; D054714:Echinocandins; D005656:Fungal Proteins; D055666:Lipopeptides; C019419:alpha-hydroxyisocaproic acid; D000077336:Caspofungin; D000079:Acetaldehyde