Amino acid biosynthetic routes as drug targets for pulmonary fungal pathogens: what is known and why do we need to know more?

Abstract

Amongst 1.5 million fatal mycoses of humans occurring annually [1], the vast majority involve the human lung as the primary site of pathogenesis, and are derived from organisms which occupy environmental niches. On entry into the respiratory system pathogenic fungi must draw upon metabolic versatility for survival and proliferation as the mammalian lung is a nutritionally limiting environment. The nutritional stresses encountered have exposed vulnerabilities which have long been viewed as potential antifungal targets, since humans lack several of the metabolic pathways which fungi rely upon for pathogenic growth. However the ability of saprophytic fungi to proteolytically liberate amino acids from exogenous protein sources, and the differential availabilities of amino acids in diverse host niches have undermined confidence in amino acid metabolism as a target for selectively toxic antifungal therapies. Recent studies have reopened this debate by revealing a number of anabolic amino acid pathways in pathogenic fungi as being essential for viability per se. This review examines new knowledge on fungal amino acid metabolism in fungal pathogens of the human lung with a view to highlighting important new advances and gaps in understanding.