Histoplasma capsulatum yeasts reside and proliferate within the macrophage phagosome during infection. This nutrient-depleted phagosomal environment imposes challenges to yeasts for nutrition acquisition. yeasts require all 20 amino acids, which can be formed by biosynthesis and/or acquired directly from the phagosomal environment. We investigated how obtains aromatic amino acids (i.e., phenylalanine, tyrosine, and tryptophan) within the phagosome during infection of macrophages. Depletion of key enzymes of the phenylalanine or tyrosine biosynthetic pathway neither impaired 's ability to proliferate within macrophages nor resulted in attenuated virulence . However, loss of tryptophan biosynthesis resulted in reduced growth within macrophages and severely attenuated virulence . Together, these results indicate that phenylalanine and tyrosine, but not tryptophan, are available to within the macrophage phagosome. The herbicide glyphosate, which targets 5-enolpyruvylshikimate-3-phosphate synthase of the aromatic amino acid biosynthetic pathway, inhibited yeast growth, and this growth inhibition was partially reversed by aromatic amino acid supplementation or overexpression of . These results suggest that the aromatic amino acid biosynthetic pathway is a candidate drug target to develop novel antifungal therapeutics.
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| http://dx.doi.org/10.1128/iai.00059-23 | DOI Listing |
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