Biology subjects

Duarte, A. G.

Publications and source records attributed to Duarte, A. G..

3 recordsLinked to original sources

bioRxiv2024

Caspofungin binding to iron compromises its antifungal efficacy against Candida albicans

Echinocandin drugs, such as caspofungin, inhibit the synthesis of {beta}-1,3-D-glucans, which are essential components of the fungal cell wall. These drugs are often the preferred option for treating invasive fungal infections (IFIs) caused by Candida spp. due to their superior efficacy compared to other antifungal agents. Iron overload conditions, which exacerbate fungal burden, are well-documented as significant risk factors for the progression of IFIs. Recent in vitro studies have suggested that iron overload may also reduce the efficacy of cell wall-perturbing agents, such as echinocandins, against Candida albicans, by altering the composition of the fungal cell wall. Here, we show that iron loading conditions which do not interfere with the cell wall composition are still capable of recapitulating the caspofungin-resistant phenotype induced by iron in C. albicans. Spectroscopic analyses provided evidence that caspofungin binds to iron through its ethylenediamine moiety and two amide groups. Consistent with the in vitro activity of {beta}-1,3-D-glucan synthase, molecular dynamics simulations revealed that, when bound to iron, caspofungin undergoes conformational changes that may reduce its ability to inhibit the enzyme. Importantly, the in vivo antifungal efficacy of caspofungin is compromised in a Galleria mellonella model of IFI caused by C. albicans simulating a context of iron overload. This effect may extend beyond C. albicans infections, as the antagonism between iron and caspofungin was also observed in other medically important fungi causing IFIs.

microbiology↗

bioRxiv2023

Structure of a membrane-bound menaquinol:organohalide oxidoreductase

Organohalide-respiring bacteria are key organisms for the bioremediation of soils and aquifers contaminated with halogenated organic compounds. The major players in this process are respiratory reductive dehalogenases, corrinoid enzymes that use organohalides as substrates and contribute to energy conservation. Here, we present the first structure of a functional menaquinol:organohalide oxidoreductase (MOOR) obtained by cryo-EM. The membrane-bound protein was isolated from Desulfitobacterium hafniense strain TCE1 as a PceA2B2 complex catalysing the dechlorination of tetrachloroethene (PCE). Two catalytic PceA subunits are anchored to the membrane by two small integral membrane PceB subunits. The structure reveals two menaquinone molecules bound at the interface of the two different subunits, which are the starting point of a chain of redox cofactors for electron transfer to the active site. This structure elucidates how energy is conserved during organohalide respiration in menaquinone-dependent organohalide-respiring bacteria.

microbiology↗

bioRxiv2023

Role of the inner membrane cytochrome ImcH in Geobacter extracellular electron transfer and energy conservation

Electroactive bacteria combine the oxidation of carbon substrates with an extracellular electron transfer (EET) process that discharges electrons to an electron acceptor outside the cell. This process involves electron transfer through consecutive redox proteins that efficiently connect the inner membrane to the cell exterior. In this study, we isolated and characterized the quinone-interacting membrane cytochrome c ImcH from Geobacter sulfurreducens, which is involved in the EET process to high redox potential acceptors. Our work provides evidence that ImcH is electroneutral, as it transfers electrons and protons to the same side of the membrane, contributing to the maintenance of a proton motive force, and plays a central role in recycling the menaquinone pool. ImportanceGeobacter sulfurreducens is a model electroactive bacterium, widespread in the environment and of significant interest for biotechnological applications. Its ability to form thick and conductive biofilms on top of conducting surfaces makes this microbe very useful in bioelectrochemical systems for the production of energy or added value products. To explore Geobacter spp. as a biocatalyst it is essential to understand its metabolism, particularly the molecular mechanisms for extracellular electron transfer and energy conservation. Our results reveal the importance of ImcH in both processes, identifying this protein as a major player on Geobacter metabolism.

biochemistry↗