Potential of Gallium as an Antifungal Agent

Bastos, Rafael Wesley; Rossato, Luana; Valero, Clara; Lagrou, Katrien; Colombo, Arnaldo Lopes; Goldman, Gustavo H.

doi:10.3389/fcimb.2019.00414

Cited by 32 publications

(44 citation statements)

References 36 publications

(52 reference statements)

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“…A link between iron chelation and caspofungin susceptibility has also been observed (59,60). Gallium is a metal compound that can be taken up by cellular iron transport systems, replacing it in iron-containing proteins.…”

Section: Discussionmentioning

confidence: 99%

“…Gallium is a metal compound that can be taken up by cellular iron transport systems, replacing it in iron-containing proteins. However, it cannot be reduced under physiological conditions, inhibiting the functionality of gallium-complexed proteins and arresting growth (59). We demonstrated previously that gallium nitrate III [Ga(NO 3 ) 3 ] has a synergistic effect with caspofungin but not with azoles and that it impairs CPE (59).…”

Section: Discussionmentioning

confidence: 99%

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Aspergillus fumigatus Transcription Factors Involved in the Caspofungin Paradoxical Effect

Valero

Colabardini

Chiaratto

et al. 2020

mBio

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Aspergillus fumigatus is the leading cause of pulmonary fungal diseases. Azoles have been used for many years as the main antifungal agents to treat and prevent invasive aspergillosis. However, in the last 10 years there have been several reports of azole resistance in A. fumigatus and new strategies are needed to combat invasive aspergillosis. Caspofungin is effective against other human-pathogenic fungal species, but it is fungistatic only against A. fumigatus. Resistance to caspofungin in A. fumigatus has been linked to mutations in the fksA gene that encodes the target enzyme of the drug β-1,3-glucan synthase. However, tolerance of high caspofungin concentrations, a phenomenon known as the caspofungin paradoxical effect (CPE), is also important for subsequent adaptation and drug resistance evolution. Here, we identified and characterized the transcription factors involved in the response to CPE by screening an A. fumigatus library of 484 null transcription factors (TFs) in CPE drug concentrations. We identified 11 TFs that had reduced CPE and that encoded proteins involved in the basal modulation of the RNA polymerase II initiation sites, calcium metabolism, and cell wall remodeling. One of these TFs, FhdA, was important for mitochondrial respiratory function and iron metabolism. The ΔfhdA mutant showed decreased growth when exposed to Congo red or to high temperature. Transcriptome sequencing (RNA-seq) analysis and further experimental validation indicated that the ΔfhdA mutant showed diminished respiratory capacity, probably affecting several pathways related to the caspofungin tolerance and resistance. Our results provide the foundation to understand signaling pathways that are important for caspofungin tolerance and resistance. IMPORTANCE Aspergillus fumigatus, one of the most important human-pathogenic fungal species, is able to cause aspergillosis, a heterogeneous group of diseases that presents a wide range of clinical manifestations. Invasive pulmonary aspergillosis is the most serious pathology in terms of patient outcome and treatment, with a high mortality rate ranging from 50% to 95% primarily affecting immunocompromised patients. Azoles have been used for many years as the main antifungal agents to treat and prevent invasive aspergillosis. However, there were several reports of evolution of clinical azole resistance in the last decade. Caspofungin, a noncompetitive β-1,3-glucan synthase inhibitor, has been used against A. fumigatus, but it is fungistatic and is recommended as second-line therapy for invasive aspergillosis. More information about caspofungin tolerance and resistance is necessary in order to refine antifungal strategies that target the fungal cell wall. Here, we screened a transcription factor (TF) deletion library for TFs that can mediate caspofungin tolerance and resistance. We have identified 11 TFs that are important for caspofungin sensitivity and/or for the caspofungin paradoxical effect (CPE). These TFs encode proteins involved in the basal modulation of the RNA polymerase II initiation sites, calcium metabolism or cell wall remodeling, and mitochondrial respiratory function. The study of those genes regulated by TFs identified in this work will provide a better understanding of the signaling pathways that are important for caspofungin tolerance and resistance.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Aspergillus fumigatus Transcription Factors Involved in the Caspofungin Paradoxical Effect

Valero

Colabardini

Chiaratto

et al. 2020

mBio

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“…Recently, Goldman et al evaluated the potential of gallium, already known for its antibacterial activity, as antifungal [ 157 ]. They demonstrated that gallium nitrate had a fungistatic action against fungi.…”

Section: Metal Metal Complexes and Metalloidsmentioning

confidence: 99%

Promising Drug Candidates and New Strategies for Fighting against the Emerging Superbug Candida auris

et al. 2021

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Invasive fungal infections represent an expanding threat to public health. During the past decade, a paradigm shift of candidiasis from Candida albicans to non-albicans Candida species has fundamentally increased with the advent of Candida auris. C. auris was identified in 2009 and is now recognized as an emerging species of concern and underscores the urgent need for novel drug development strategies. In this review, we discuss the genomic epidemiology and the main virulence factors of C. auris. We also focus on the different new strategies and results obtained during the past decade in the field of antifungal design against this emerging C. auris pathogen yeast, based on a medicinal chemist point of view. Critical analyses of chemical features and physicochemical descriptors will be carried out along with the description of reported strategies.

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“… * Antifungal susceptibility testing was interpreted according to the document M27-S3 published by CLSI; n , number of fungal isolates; the references used to construct this table were [ 5 , 7 , 25 , 29 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 ]. …”

Section: Figurementioning

confidence: 99%

“… a CAS, caspofungin; MCF, micafungin; ANF, anidulafungin; b MIC 50 , MIC at which 50% of isolates were inhibited; c MIC 90 , MIC at which 90% of isolates were inhibited; Modal MICs are indicated with underlined numbers; MIC values of <0.03 were allocated as ≤0.015; Clinical and Laboratory Standards Institute (CLSI) document M27S3 suggests the following breakpoints for echinocandins against Candida spp. : susceptible ≤ 2 mg/L and non-susceptible > 2 mg/L; the references used to construct this table were [ 5 , 29 , 31 , 34 , 35 , 38 , 39 , 40 , 41 , 42 , 44 , 46 , 47 ]. …”

Section: Figurementioning

confidence: 99%

Susceptibility of the Candida haemulonii Complex to Echinocandins: Focus on Both Planktonic and Biofilm Life Styles and a Literature Review

Ramos

Silva

Branquinha

et al. 2020

JoF

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Candida haemulonii complex (C. haemulonii, C. duobushaemulonii and C. haemulonii var. vulnera) is well-known for its resistance profile to different available antifungal drugs. Although echinocandins are the most effective class of antifungal compounds against the C. haemulonii species complex, clinical isolates resistant to caspofungin, micafungin and anidulafungin have already been reported. In this work, we present a literature review regarding the effects of echinocandins on this emergent fungal complex. Published data has revealed that micafungin and anidulafungin were more effective than caspofungin against the species forming the C. haemulonii complex. Subsequently, we investigated the susceptibilities of both planktonic and biofilm forms of 12 Brazilian clinical isolates of the C. haemulonii complex towards caspofungin and micafungin (anidulafungin was unavailable). The planktonic cells of all the fungal isolates were susceptible to both of the test echinocandins. Interestingly, echinocandins caused a significant reduction in the biofilm metabolic activity (viability) of almost all fungal isolates (11/12, 91.7%). Generally, the biofilm biomasses were also affected (reduction range 20–60%) upon exposure to caspofungin and micafungin. This is the first report of the anti-biofilm action of echinocandins against the multidrug-resistant opportunistic pathogens comprising the C. haemulonii complex, and unveils the therapeutic potential of these compounds.

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Potential of Gallium as an Antifungal Agent

Cited by 32 publications

References 36 publications

Aspergillus fumigatus Transcription Factors Involved in the Caspofungin Paradoxical Effect

Aspergillus fumigatus Transcription Factors Involved in the Caspofungin Paradoxical Effect

Promising Drug Candidates and New Strategies for Fighting against the Emerging Superbug Candida auris

Susceptibility of the Candida haemulonii Complex to Echinocandins: Focus on Both Planktonic and Biofilm Life Styles and a Literature Review

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