Pan-active imidazolopiperazine antimalarials target the Plasmodium falciparum intracellular secretory pathway.

A promising new compound class for treating human malaria is the imidazolopiperazines (IZP) class. IZP compounds KAF156 (Ganaplacide) and GNF179 are effective against Plasmodium symptomatic asexual blood-stage infections, and are able to prevent transmission and block infection in animal models. But despite the identification of resistance mechanisms in P. falciparum, the mode of action of IZPs remains unknown. To investigate, we here combine in vitro evolution and genome analysis in Saccharomyces cerevisiae with molecular, metabolomic, and chemogenomic methods in P. falciparum. Our findings reveal that IZP-resistant S. cerevisiae clones carry mutations in genes involved in Endoplasmic Reticulum (ER)-based lipid homeostasis and autophagy. In Plasmodium, IZPs inhibit protein trafficking, block the establishment of new permeation pathways, and cause ER expansion. Our data highlight a mechanism for blocking parasite development that is distinct from those of standard compounds used to treat malaria, and demonstrate the potential of IZPs for studying ER-dependent protein processing

Clinical features and outcomes of patients with myasthenia gravis admitted to an intensive care unit: A 20-year retrospective study

Background. There are limited data on the clinical characteristics and outcomes of patients with myasthenia gravis (MG) admitted to the intensive care unit (ICU) at Charlotte Maxeke Johannesburg Academic Hospital (CMJAH). Objectives. The aim was to study the clinical characteristics and outcomes of patients with MG admitted to the CMJAH over two decades. Methods. A retrospective study was undertaken of patients with MG admitted to the multidisciplinary ICU of CMJAH over a 20-year period, from 1998 to 2017. Demographic data, clinical features, management and outcomes of patients were assessed and reviewed from the case records. Results. Thirty-four patients with MG were admitted to the ICU during this period: 24 female and 10 male. The mean age ± SD was 37.4 ± 13.0 years, with a range of 16 - 66 years. Four patients were human immunodeficiency virus (HIV)-positive. The mean length of stay (LOS) in ICU was 10.6 ± 20.1 days, ranging from 1 to 115 days. Two patients were diagnosed with MG in the ICU after failure to wean from the ventilator. Overall, 22 patients were intubated and ventilated on admission. Morbidities included self-extubation, aspiration pneumonia and iatrogenic pneumothorax. History of thymectomy was present in 12 patients. The treatments received for MG included pyridostigmine (73.5%), corticosteroids (55.9%), azathioprine (35.3%), plasmapheresis (26.5%) and intravenous immunoglobulin (8.8%). The overall mortality in the ICU was 5.9%. Conclusion. MG is a serious disorder with considerable morbidity and mortality. It is, however, a potentially manageable disease, provided that appropriate ICU resources are available

Pan-active imidazolopiperazine antimalarials target the Plasmodium falciparum intracellular secretory pathway

A promising new compound class for treating human malaria is the imidazolopiperazines (IZP) class. IZP compounds KAF156 (Ganaplacide) and GNF179 are effective against Plasmodium symptomatic asexual blood-stage infections, and are able to prevent transmission and block infection in animal models. But despite the identification of resistance mechanisms in P. falciparum, the mode of action of IZPs remains unknown. To investigate, we here combine in vitro evolution and genome analysis in Saccharomyces cerevisiae with molecular, metabolomic, and chemogenomic methods in P. falciparum. Our findings reveal that IZP-resistant S. cerevisiae clones carry mutations in genes involved in Endoplasmic Reticulum (ER)-based lipid homeostasis and autophagy. In Plasmodium, IZPs inhibit protein trafficking, block the establishment of new permeation pathways, and cause ER expansion. Our data highlight a mechanism for blocking parasite development that is distinct from those of standard compounds used to treat malaria, and demonstrate the potential of IZPs for studying ER-dependent protein processing