Carbonic anhydrase inhibitors. Inhibition of the β-class enzymes from the fungal pathogens Candida albicans and Cryptococcus neoformans with aliphatic and aromatic carboxylates

ABSTRACTSimilarities in fungal and animal cells make antifungal discovery efforts more difficult than those for other classes of antimicrobial drugs. Currently, there are only three major classes of antifungal drugs used for the treatment of systemic fungal diseases: polyenes, azoles, and echinocandins. Even in situations where the offending fungal organism is susceptible to the available drugs, treatment courses can be lengthy and unsatisfactory, since eradication of infection is often very difficult, especially in individuals with impaired immunity. Consequently, there is a need for new and more effective antifungal drugs. We have identified compounds with significant antifungal activity in the Malaria Box (Medicines for Malaria Ventures, Geneva, Switzerland) that have higher efficacy than some of the currently used antifungal drugs. Our best candidate, MMV665943 (IUPAC name 4-[6-[[2-(4-aminophenyl)-3H-benzimidazol-5-yl]methyl]-1H-benzimidazol-2-yl]aniline), here referred to as DM262, showed 16- to 32-fold-higher activity than fluconazole againstCryptococcus neoformans. There was also significant antifungal activity in other fungal species with known antifungal resistance, such asLomentospora prolificansandCryptococcus gattii. Antifungal activity was also observed against a common fungus,Candida albicans. These results are important because they offer a potentially new class of antifungal drugs and the repurposing of currently available therapeutics.IMPORTANCEMuch like the recent increase in drug-resistant bacteria, there is a rise in antifungal-resistant strains of pathogenic fungi. There is a need for novel and more potent antifungal therapeutics. Consequently, we investigated a mixed library of drug-like and probe-like compounds with activity inPlasmodiumspp. for activity against two common fungal pathogens,Cryptococcus neoformansandCandida albicans, along with two less common pathogenic species,Lomentospora prolificansandCryptococcus gattii. We uncover a previously uncharacterized drug with higher broad-spectrum antifungal activity than some current treatments. Our findings may eventually lead to a compound added to the arsenal of antifungal therapeutics.

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Chromatin-Mediated Regulation of Genome Plasticity in Human Fungal Pathogens

Genes ◽

10.3390/genes10110855 ◽

2019 ◽

Vol 10 (11) ◽

pp. 855 ◽

Cited By ~ 3

Author(s):

Buscaino

Keyword(s):

Candida Albicans ◽

Aspergillus Fumigatus ◽

Cryptococcus Neoformans ◽

Fungal Pathogens ◽

Environmental Changes ◽

Structure And Function ◽

Model Systems ◽

Genome Plasticity ◽

And Function ◽

Heterochromatin Structure

Human fungal pathogens, such as Candida albicans, Aspergillus fumigatus and Cryptococcus neoformans, are a public health problem, causing millions of infections and killing almost half a million people annually. The ability of these pathogens to colonise almost every organ in the human body and cause life-threating infections relies on their capacity to adapt and thrive in diverse hostile host-niche environments. Stress-induced genome instability is a key adaptive strategy used by human fungal pathogens as it increases genetic diversity, thereby allowing selection of genotype(s) better adapted to a new environment. Heterochromatin represses gene expression and deleterious recombination and could play a key role in modulating genome stability in response to environmental changes. However, very little is known about heterochromatin structure and function in human fungal pathogens. In this review, I use our knowledge of heterochromatin structure and function in fungal model systems as a road map to review the role of heterochromatin in regulating genome plasticity in the most common human fungal pathogens: Candida albicans, Aspergillus fumigatus and Cryptococcus neoformans.

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Carbonic anhydrase activators: Activation of the β-carbonic anhydrases from the pathogenic fungi Candida albicans and Cryptococcus neoformans with amines and amino acids

Bioorganic & Medicinal Chemistry ◽

10.1016/j.bmc.2009.12.058 ◽

2010 ◽

Vol 18 (3) ◽

pp. 1034-1037 ◽

Cited By ~ 14

Author(s):

Alessio Innocenti ◽

Rebecca A. Hall ◽

Andrea Scozzafava ◽

Fritz A. Mühlschlegel ◽

Claudiu T. Supuran

Keyword(s):

Amino Acids ◽

Candida Albicans ◽

Carbonic Anhydrase ◽

Cryptococcus Neoformans ◽

Pathogenic Fungi ◽

Carbonic Anhydrases

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Discovery of a Novel Antifungal Agent in the Pathogen Box

mSphere ◽

10.1128/msphere.00120-17 ◽

2017 ◽

Vol 2 (2) ◽

Cited By ~ 23

Author(s):

François L. Mayer ◽

James W. Kronstad

Keyword(s):

Candida Albicans ◽

Cryptococcus Neoformans ◽

High Mortality ◽

Fungal Pathogens ◽

Mortality Rates ◽

Lead Compound ◽

Content Type ◽

Novel Drugs ◽

Very High ◽

Hiv Aids

ABSTRACT Cryptococcus neoformans and Candida albicans are two major human fungal pathogens and together account for over 1.4 million infections annually, with very high mortality rates. These fungi often infect immunocompromised individuals, such as HIV/AIDS patients. In an effort to identify novel drugs with antifungal activity, we have screened the Pathogen Box for compounds with anticryptococcal and anticandidal activities. This approach led to the discovery of a promising lead compound (MMV688271) with strong antifungal potency under nutrient-limited conditions. Human fungal pathogens cause over 2 million infections per year and are major drivers of morbidity and mortality. Cryptococcus neoformans and Candida albicans are two of the most common fungal pathogens of humans, together accounting for a staggering 1.4 million infections annually, with very high mortality rates. Patients with dysfunctional immune systems, such as individuals with HIV/AIDS, are particularly susceptible to fungal infections. Unfortunately, relatively few antifungal drugs are currently available and fungi frequently develop resistance, further complicating treatment approaches. In this study, we screened the Pathogen Box chemical library (Medicines for Malaria Venture, Switzerland) in an effort to identify novel antifungal compounds. This approach led to the discovery of a novel, highly potent antifungal agent with activity against both C. neoformans and C. albicans. Our initial study of the mechanism of action suggested that this novel compound prevents fungal proliferation by targeting the ability of C. neoformans to withstand stress at the plasma membrane and cell wall. Because this compound had previously been shown to have low toxicity for mammalian cells, we propose that it represents an attractive lead compound for further antifungal drug development. IMPORTANCE Cryptococcus neoformans and Candida albicans are two major human fungal pathogens and together account for over 1.4 million infections annually, with very high mortality rates. These fungi often infect immunocompromised individuals, such as HIV/AIDS patients. In an effort to identify novel drugs with antifungal activity, we have screened the Pathogen Box for compounds with anticryptococcal and anticandidal activities. This approach led to the discovery of a promising lead compound (MMV688271) with strong antifungal potency under nutrient-limited conditions.

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Disarming Fungal Pathogens:Bacillus safensisInhibits Virulence Factor Production and Biofilm Formation byCryptococcus neoformansandCandida albicans

mBio ◽

10.1128/mbio.01537-17 ◽

2017 ◽

Vol 8 (5) ◽

Cited By ~ 24

Author(s):

François L. Mayer ◽

James W. Kronstad

Keyword(s):

Cell Wall ◽

Candida Albicans ◽

Cryptococcus Neoformans ◽

Virulence Factors ◽

Virulence Factor ◽

Biofilm Formation ◽

Fungal Pathogens ◽

Soil Bacterium ◽

Fungal Cell ◽

Virulence Factor Production

ABSTRACTBacteria interact with each other in nature and often compete for limited nutrient and space resources. However, it is largely unknown whether and how bacteria also interact with human fungal pathogens naturally found in the environment. Here, we identified a soil bacterium,Bacillus safensis, which potently blocked several keyCryptococcus neoformansvirulence factors, including formation of the antioxidant pigment melanin and production of the antiphagocytic polysaccharide capsule. The bacterium also inhibitedde novocryptococcal biofilm formation but had only modest inhibitory effects on already formed biofilms or planktonic cell growth. The inhibition of fungal melanization was dependent on direct cell contact and live bacteria.B. safensisalso had anti-virulence factor activity against another major human-associated fungal pathogen,Candida albicans. Specifically, dual-species interaction studies revealed that the bacterium strongly inhibitedC. albicansfilamentation and biofilm formation. In particular,B. safensisphysically attached to and degraded candidal filaments. Through genetic and phenotypic analyses, we demonstrated that bacterial chitinase activity against fungal cell wall chitin is a factor contributing to the antipathogen effect ofB. safensis.IMPORTANCEPathogenic fungi are estimated to contribute to as many human deaths as tuberculosis or malaria. Two of the most common fungal pathogens,Cryptococcus neoformansandCandida albicans, account for up to 1.4 million infections per year with very high mortality rates. Few antifungal drugs are available for treatment, and development of novel therapies is complicated by the need for pathogen-specific targets. Therefore, there is an urgent need to identify novel drug targets and new drugs. Pathogens use virulence factors during infection, and it has recently been proposed that targeting these factors instead of the pathogen itself may represent a new approach to develop antimicrobials. Here, we identified a soil bacterium that specifically blocked virulence factor production and biofilm formation byC. neoformansandC. albicans. We demonstrate that the bacterial antipathogen mechanism is based in part on targeting the fungal cell wall, a structure not found in human cells.

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Macrophage Autophagy in Immunity to Cryptococcus neoformans and Candida albicans

Infection and Immunity ◽

10.1128/iai.00358-12 ◽

2012 ◽

Vol 80 (9) ◽

pp. 3065-3076 ◽

Cited By ~ 71

Author(s):

André Moraes Nicola ◽

Patrícia Albuquerque ◽

Luis R. Martinez ◽

Rafael Antonio Dal-Rosso ◽

Carolyn Saylor ◽

...

Keyword(s):

Candida Albicans ◽

Cryptococcus Neoformans ◽

Fungal Pathogens ◽

Cytokine Signaling ◽

Alternatively Activated Macrophages ◽

Content Type ◽

Material Recycling ◽

Fungistatic Activity ◽

Increased Susceptibility

ABSTRACTAutophagy is used by eukaryotes in bulk cellular material recycling and in immunity to intracellular pathogens. We evaluated the role of macrophage autophagy in the response toCryptococcus neoformansandCandida albicans, two important opportunistic fungal pathogens. The autophagosome marker LC3 (microtubule-associated protein 1 light chain 3 alpha) was present in most macrophage vacuoles containingC. albicans. In contrast, LC3 was found in only a few vacuoles containingC. neoformanspreviously opsonized with antibody but never after complement-mediated phagocytosis. Disruption of host autophagyin vitroby RNA interference against ATG5 (autophagy-related 5) decreased the phagocytosis ofC. albicansand the fungistatic activity of J774.16 macrophage-like cells against both fungi, independent of the opsonin used. ATG5-knockout bone marrow-derived macrophages (BMMs) also had decreased fungistatic activity againstC. neoformanswhen activated. In contrast, nonactivated ATG5-knockout BMMs actually restrictedC. neoformansgrowth more efficiently, suggesting that macrophage autophagy plays different roles againstC. neoformans, depending on the macrophage type and activation. Interference with autophagy in J774.16 cells also decreased nonlytic exocytosis ofC. neoformans, increased interleukin-6 secretion, and decreased gamma interferon-induced protein 10 secretion. Mice with a conditionally knocked out ATG5 gene in myeloid cells showed increased susceptibility to intravenousC. albicansinfection. In contrast, these mice manifested no increased susceptibility toC. neoformans, as measured by survival, but had fewer alternatively activated macrophages and less inflammation in the lungs after intratracheal infection than control mice. These results demonstrate the complex roles of macrophage autophagy in restricting intracellular parasitism by fungi and reveal connections with nonlytic exocytosis, humoral immunity, and cytokine signaling.

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