Antiepileptic Drugs Inhibit Growth, Dimorphism, and Biofilm Mode of Growth in Human Pathogen Candida albicans Gunderao H. Kathwate, Ravikumar B. Shinde, and S. Mohan Karuppayil DST-FIST- and UGC-SAP-Sponsored School of Life Sciences, Swami Ramanand Teerth Marathwada University, Nanded, Maharashtra, India. ABSTRACT Exploring the potential of existing drugs for their unknown properties may offer advantages over conventional drug devel- opment by saving time and money. Candida albicans, an im- portant human opportunist, shares many genetic properties with humans. This has encouraged us to study drugs that are not originally antifungals against C. albicans. In the present study, we have tested six antiepileptic drugs for their activities against C. albicans. Their effects on growth, time-dependent killing, yeast-to-hyphal form switching, and biofilms formation by C. albicans were studied. Out of the drugs studied, four drugs, which are c-aminobutyric acid (GABA) receptor agonists in humans, inhibited growth, yeast-to-hyphal form switching, and biofilm formation in C. albicans. Lorazepam inhibited growth of C. albicans at 25 lg/ml, followed by midazolam and diazepam (minimum inhibitory concentrations 100 and 400 lg/ml, re- spectively). Members from other group voltage-gated sodium channel blockers failed to inhibit C. albicans. Our study has identified GABA receptor agonists used in epileptic therapy as potential candidates for antifungal drug development against the human pathogen C. albicans. INTRODUCTION T here have been increasing incidences of brain men- ingitis due to opportunistic fungal pathogen Candida albicans. Four to fifteen percent of neonatal candide- mia cases occur in extremely low-birth-weight in- fants, 1,2 and 4% infants are with Candida meningitis with brain abscess. 3 In the patients with candidiasis, 5–9% are with Can- dida meningitis. 2 The ability of antifungal drugs to achieve adequate concentration in the brain is one of the major factors that affect the success of treatment. Possible reasons for the failure to achieve effective concentration may be high molec- ular weight, low lipophilicity, high affinity for plasma proteins, high affinity to efflux pump, and molecular charge. 4 In- sufficient selective agents and emergence of clinical resistance demand development of new antifungal agents. Development cost and failure rate of the new potential drugs in or before reaching the clinics is a big concern to the drug developers. An alternative approach for discovering new agents is to find new uses for existing drugs. Such approach is termed as drug repositioning or repurposing. 5,6 Candida, being a eu- karyote, shares many common targets with humans. Drugs used in antiepileptic disorders (AED) easily cross the blood– brain barrier. In this study we have explored the antifungal properties of drugs used in AED. There are two classes of drugs used against epileptic disorder, namely, voltage-gated sodium channel (VGSC) blockers and g-aminobutyric acid (GABA) receptor agonists. VGSCs depolarize the nerve cell membrane and conduct action potentials across the surface of neuronal cells. 7 VGSC blockers have the highest affinity for resting state channel proteins. Their binding slows down the retention of channel conformation, resulting in a limited re- petitive neuronal firing. Enzyme glutamic acid decarboxylase converts glutamate to GABA. It is released from GABAergic nerve terminals and inhibits both GABA A and GABA B recep- tors causing hyperpolarization. 8 In AED, GABA secretions get inhibited. Functionally, GABA receptor agonists like barbitu- rates increase the time lap of chloride channel opening, while benzodiazepines increase the frequency of opening. Barbitu- rates also have the ability to activate GABA A receptors in the absence of GABA. 9 In the present communication, we at- tempted to reposition antiepileptic agents as anti-Candida agents. Their activities against selected virulence factors are reported. MATERIALS AND METHODS Cultures Two standard strains of C. albicans, ATCC 10231 and ATCC 90028 cultures, were obtained from IMTECH Chandigarh, India. Cultures were maintained on YPD agar slant at 4°C. DOI: 10.1089/adt.2015.29007.ghkdrrr ª MARY ANN LIEBERT, INC.  VOL. 13 NO. 6  JULY/AUGUST 2015 ASSAY and Drug Development Technologies 307