Hydroxyurea treatment inhibits proliferation of Cryptococcus neoformans in mice

Abstract

The fungal pathogen Cryptococcus neoformans (Cn) is a serious threat to immunocompromised individuals, especially for HIV patients who develop meningoencephalitis. For effective cryptococcal treatment, novel antifungal drugs or innovative combination therapies are needed. Recently, sphingolipids have emerged as important bioactive molecules in the regulation of microbial pathogenesis. Previously we reported that the sphingolipid pathway gene, ISC1, which is responsible for ceramide production, is a major virulence factor in Cn infection. Here we report our studies of the role of ISC1 during genotoxic stress induced by the antineoplastic hydroxyurea (HU) and methyl methanesulfonate (MMS), which affect DNA replication and genome integrity. We observed that Cn cells lacking ISC1 are highly sensitive to HU and MMS in a rich culture medium. HU affected cell division of Cn cells lacking the ISC1 gene, resulting in cell clusters. Cn ISC1, when expressed in a Saccharomyces cerevisiae (Sc) strain lacking its own ISC1 gene, restored HU resistance. In macrophage-like cells, although HU affected the proliferation of wild type (WT) Cn cells by 50% at the concentration tested, HU completely inhibited Cn isc1Δ cell proliferation. Interestingly, our preliminary data show that mice infected with WT or Cn isc1Δ cells and subsequently treated with HU had longer lifespans than untreated, infected control mice. Our work suggests that the sphingolipid pathway gene, ISC1, is a likely target for combination therapy with traditional drugs such as HU.

Cryptococcus Neoformans Infection and Immune Cell Regulation in Human Monocytes

“…PBMC was recovered, washed twice in RPMI 1640 supplement, and incubated for 1 hour at a concentration of 2×10 7 to 3×10…”

“…In the later stages of AIDS, the uncontrolled dispersal of C. neoformans in the lungs can cause severe and highly recurrent meningoencephalitis, which affects approximately 4-8% of AIDS patients [4]. Despite progress in the development of novel antifungal therapies, these treatments have not completely eradicated C. neoformans infection [5][6][7]. The difficulty in eradicating this organism lies in the intrinsic properties of its capsule, which can possibly explain the reasons behind its persistence and recurrence.…”

Novel imidazo[2,1-b]-1,3,4-thiadiazoles as promising antifungal agents against clinical isolate of Cryptococcus neoformans

“…Candida, Cryptococcus and Aspergillus species) have developed drastic resistance. Patients with significant immunosuppression frequently develop Cryptococcosis, which is caused by the encapsulated yeast Cryptococcus neoformans and is responsible for serious clinical illnesses like lung infections, fungal meningitis and encephalitis [3]. It spreads by gulping aerosolized spores which may enter the pulmonary or the central nervous system [4].…”

“…The completion of reaction was monitored by TLC using ethyl acetate and hexane (1:3). The solid thus obtained was filtered, dried and recrystallized using the suitable solvent to afford the Schiff base derivatives (6a-j) of imidazo[2, 1-b][1,3,4]thiadiazoles.…”

Vaccines and immunotherapy against fungi: the new frontier

“…Finally, new information about the antifungal activity of "old" drugs is discussed. Hydroxyurea is shown to impact the sphingolipid pathway underscoring the role of these compounds in fungal biology (Tripathi et al, 2012). The diverse activities of Amphotericin B on both fungi, impacting ergosterol stability and cellular morphology, and host cells, engaging pattern receptors, is critically summarized (Mesa-Arango et al, 2012).…”