<i>In vivo veritas: Aspergillus fumigatus</i>proliferation and pathogenesis – conditionally speaking

Cramer, Robert A.

doi:10.1080/21505594.2015.1134074

Cited by 9 publications

(7 citation statements)

References 36 publications

(40 reference statements)

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“…However, antifungal drugs are normally administered to treat patients who already have an established infection. Therefore, it is possible that the conditional essentiality of the gene could be overcome when the fungus is actively growing in the tissue, since the fungal metabolic requirements and the environmental conditions are different (53,54). Consequently, in order to achieve a rigorous target validation, it is crucial to assess the efficiency of new target candidates in established infections.…”

Section: Fungal Methionine Synthase In Vivo Target Validationmentioning

confidence: 99%

Targeting Methionine Synthase in a Fungal Pathogen Causes a Metabolic Imbalance That Impacts Cell Energetics, Growth, and Virulence

Scott

Sueiro-Olivares

Thornton

et al. 2020

mBio

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There is an urgent need to develop novel antifungals to tackle the threat fungal pathogens pose to human health. Here, we have performed a comprehensive characterization and validation of the promising target methionine synthase (MetH). We show that in Aspergillus fumigatus the absence of this enzymatic activity triggers a metabolic imbalance that causes a reduction in intracellular ATP, which prevents fungal growth even in the presence of methionine. Interestingly, growth can be recovered in the presence of certain metabolites, which shows that metH is a conditionally essential gene and consequently should be targeted in established infections for a more comprehensive validation. Accordingly, we have validated the use of the tetOFF genetic model in fungal research and improved its performance in vivo to achieve initial validation of targets in models of established infection. We show that repression of metH in growing hyphae halts growth in vitro, which translates into a beneficial effect when targeting established infections using this model in vivo. Finally, a structure-based virtual screening of methionine synthases reveals key differences between the human and fungal structures and unravels features in the fungal enzyme that can guide the design of novel specific inhibitors. Therefore, methionine synthase is a valuable target for the development of new antifungals. IMPORTANCE Fungal pathogens are responsible for millions of life-threatening infections on an annual basis worldwide. The current repertoire of antifungal drugs is very limited and, worryingly, resistance has emerged and already become a serious threat to our capacity to treat fungal diseases. The first step to develop new drugs is often to identify molecular targets in the pathogen whose inhibition during infection can prevent its growth. However, the current models are not suitable to validate targets in established infections. Here, we have characterized the promising antifungal target methionine synthase in great detail, using the prominent fungal pathogen Aspergillus fumigatus as a model. We have uncovered the underlying reason for its essentiality and confirmed its druggability. Furthermore, we have optimized the use of a genetic system to show a beneficial effect of targeting methionine synthase in established infections. Therefore, we believe that antifungal drugs to target methionine synthase should be pursued and additionally, we provide a model that permits gaining information about the validity of antifungal targets in established infections.

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Section: Fungal Methionine Synthase In Vivo Target Validationmentioning

confidence: 99%

Targeting Methionine Synthase in a Fungal Pathogen Causes a Metabolic Imbalance That Impacts Cell Energetics, Growth, and Virulence

Scott

Sueiro-Olivares

Thornton

et al. 2020

mBio

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“…However, antifungal drugs are normally administered to treat patients who already have an established infection. Therefore, it is possible that the conditional essentiality of the gene could be overcome when the fungus is actively growing in the tissue, as the fungal metabolic requirements and the environmental conditions are different (49,50). Consequently, in order to achieve a rigorous target validation, it is crucial to assess the efficiency of new target candidates in established infections.…”

Section: Targeting Meth In Established Infections Interferes With Thementioning

confidence: 99%

Targeting methionine synthase in a fungal pathogen causes a metabolic imbalance that impacts cell energetics, growth and virulence

Scott

Sueiro-Olivares

Thornton

et al. 2020

Preprint

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29There is an urgent need to develop novel antifungals to tackle the threat fungal pathogens pose 30 to human health. In this work, we have performed a comprehensive characterisation and 31 validation of the promising target methionine synthase (MetH). We uncover that in Aspergillus 32 fumigatus the absence of this enzymatic activity triggers a metabolic imbalance that causes a 33 reduction in intracellular ATP, which prevents fungal growth even in the presence of methionine. 34Interestingly, growth can be recovered in the presence of certain metabolites, which evidences 35 that conditional essentiality, defined as genes whose deficiency can be overcome in specific 36 conditions, is present in pathogenic fungi. As this concept must be considered for correct target 37 validation, we have optimised a genetic model to mimic treatment of established infections 38 using the tetOFF system. We show that repression of metH in growing hyphae halts growth in 39 vitro, which translates into a beneficial effect when targeting established infections using this 40 model in vivo. Finally, a structural-based virtual screening of methionine synthases reveals key 41 differences between the human and fungal structures and unravels features in the fungal 42 enzyme that can guide the design of novel specific inhibitors. Therefore, methionine synthase is 43 a valuable target for the development of new antifungals. 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59Fungal pathogens represent an increasing risk to human health 1 , with over one billion people 60 worldwide affected by mycoses annually. Many of these mycoses are superficial infections of 61 the skin, nails or mucosal membranes and although troublesome are usually not life-62 threatening. However, some fungi cause devastating chronic and invasive fungal infections, 63 which result in an estimated 1.6 million deaths per year 2 . Incidences of invasive infections 64 caused by Aspergillus, Candida, Cryptococcus and Pneumocystis species are increasing 3 , a cause 65 for serious concern as these genera are responsible for 90% of deaths caused by mycoses 4 . 66Despite the availability of antifungal drugs, mortality rates for invasive aspergillosis, invasive 67 candidiasis, cryptococcal meningitis and Pneumocystis jirovecii pneumonia are intolerably high, 68reaching over 80%, 40%, 50% and 30% respectively 2,5 . There are currently only four classes of 69 antifungals in clinical use to treat invasive infections (azoles, echinocandins, polyenes and 70 flucytosine), all suffering from pharmacological drawbacks including toxicity, drug-drug 71 interactions and poor bioavailability 6,7 . With the sole exemption of flucytosine, which is only 72 used in combinatory therapy with amphotericin B for cryptococcal meningitis and Candida 73 endocarditis 7 , the current antifungals target critical components of the fungal cell membrane 74 or cell wall 8 , which represents a very limited druggable space. The rise of antifungal resistance 75 presents an additional challenge as mortality rates in pat...

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“…Conidia produced by this fungus can stay several months to a year dormant in the environment and capable of germinating into a mesh of hyphae upon landing on an appropriate substrate. Small size and abundant number of A. fumigatus conidia found in air help them to reach into deep alveolar cavities of animals and humans (Bultman et al 2017;Cramer 2016). Especially, this landing of conidia into alveolar surfaces can lead to life threatening systemic diseases in individuals with a weakened immune system and serious allergic reactions such as Allergic broncho pulmonary aspergillosis in immunocompetent individuals (Heinekamp et al 2015;Latge 2001).…”

Section: Myba Backgroundmentioning

confidence: 99%

MybA, a new player driving survival of the conidium of the human pathogen Aspergillus fumigatus

Bayram

Latgé

2017

Curr Genet

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Aspergillus fumigatus is an opportunistic human pathogen that causes various complications in patients with a weakened immune system functions. Asexual spores of A. fumigatus are responsible for initiation of aspergillosis. Long-term viability and proper germination of dormant conidia depend on trehalose accumulation, which protect the spores against thermal and oxidative stress. A putative Myb transcription factor, MybA has been recently found to be responsible for a variety of physiological and molecular roles ranging from conidiation, spore viability, trehalose accumulation, cell wall integrity and protection against reactive oxygen species. In this perspective review, we discuss the recent findings of MybA and its overlapping functions with the other regulators of conidia viability and trehalose accumulation. Therefore, the aim of this perspective is to raise interesting and stimulating questions on the molecular functions of MybA in conidiation and trehalose biogenesis and to question its genetic and physical interactions with the other regulators of conidial viability.

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In vivo veritas: Aspergillus fumigatusproliferation and pathogenesis – conditionally speaking

Cited by 9 publications

References 36 publications

Targeting Methionine Synthase in a Fungal Pathogen Causes a Metabolic Imbalance That Impacts Cell Energetics, Growth, and Virulence

Targeting Methionine Synthase in a Fungal Pathogen Causes a Metabolic Imbalance That Impacts Cell Energetics, Growth, and Virulence

Targeting methionine synthase in a fungal pathogen causes a metabolic imbalance that impacts cell energetics, growth and virulence

MybA, a new player driving survival of the conidium of the human pathogen Aspergillus fumigatus

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