Pneumocystis jirovecii Rtt109, a Novel Drug Target for Pneumocystis Pneumonia in Immunosuppressed Humans

Abstract

ABSTRACTPneumocystispneumonia (PcP) is a significant cause of morbidity and mortality in immunocompromised patients. In humans, PcP is caused by the opportunistic fungal speciesPneumocystis jirovecii. Progress inPneumocystisresearch has been hampered by a lack of viablein vitroculture methods, which limits laboratory access to human-derived organisms for drug testing. Consequently, most basic drug discovery research forP. jiroveciiis performed using related surrogate organisms such asPneumocystis carinii, which is derived from immunosuppressed rodents. While these studies provide useful insights, important questions arise about interspecies variations and the relative utility of identified anti-Pneumocystisagents against humanP. jirovecii. Our recent work has identified the histone acetyltransferase (HAT) Rtt109 inP. carinii(i.e., PcRtt109) as a potential therapeutic target for PcP, since Rtt109 HATs are widely conserved in fungi but are absent in humans. To further address the potential utility of this target in human disease, we now demonstrate the presence of a functional Rtt109 orthologue in the clinically relevant fungal pathogenP. jirovecii(i.e., PjRtt109). In a fashion similar to that ofPcrtt109,Pjrtt109restores H3K56 acetylation and genotoxic resistance inrtt109-null yeast. Recombinant PjRtt109 is an active HATin vitro, with activity comparable to that of PcRtt109 and yeast Rtt109. PjRtt109 HAT activity is also enhanced by the histone chaperone Asf1in vitro. PjRtt109 and PcRtt109 showed similar low micromolar sensitivities to two reported small-molecule HAT inhibitorsin vitro. Together, these results demonstrate that PjRtt109 is a functional Rtt109 HAT, and they support the development of anti-Pneumocystisagents directed at Rtt109-catalyzed histone acetylation as a novel therapeutic target for human PcP.