Significance Useful antimalarial drugs must be rapidly acting, highly efficacious, and have low potential for developing resistance. (+)-SJ733 targets a Plasmodium cation-transporting ATPase, ATP4. (+)-SJ733 cleared parasites in vivo as quickly as artesunate by specifically inducing eryptosis/senescence in infected, treated erythrocytes. Although in vitro selection of pfatp4 mutants with (+)-SJ733 proceeded with moderate frequency, during in vivo selection of pbatp4 mutants, resistance emerged slowly and produced marginally resistant mutants with poor fitness. In addition, (+)-SJ733 met all other criteria for a clinical candidate, including high oral bioavailability, a high safety margin, and transmission blocking activity. These results demonstrate that targeting ATP4 has great potential to deliver useful drugs for malaria eradication.

BACKGROUND: Hospitalized pediatric hematology-oncology (PHO) patients have frequent clinical deterioration events (CDE) requiring intensive care unit (ICU) admission, particularly in resource-limited settings. The objective of this study was to describe CDEs in hospitalized PHO patients in Latin America and to identify event-level and center-level risk factors for mortality. METHODS: In 2017, the authors implemented a prospective registry of CDEs, defined as unplanned transfers to a higher level of care, use of ICU-level interventions on the floor, or nonpalliative floor deaths, in 16 PHO centers in 10 countries. PHO hospital admissions and hospital inpatient days were also reported. This study analyzes the first year of registry data (June 2017 to May 2018). RESULTS: Among 16 centers, 553 CDEs were reported in PHO patients during 11,536 admissions and 119,414 inpatient days (4.63 per 1000 inpatient days). Event mortality was 29% (1.33 per 1000 inpatient days) but ranged widely across centers (11%-79% or 0.36-5.80 per 1000 inpatient days). Significant risk factors for event mortality included requiring any ICU-level intervention on the floor and not being transferred to a higher level of care. Events with organ dysfunction, a higher severity of illness, and a requirement for ICU intervention had higher mortality. In center-level analysis, hospitals with a higher volume of PHO patients, less floor use of ICU intervention, lower severity of illness on transfer, and lower rates of floor cardiopulmonary arrest had lower event mortality. CONCLUSIONS: Hospitalized PHO patients who experience CDEs in resource-limited settings frequently require floor-based ICU interventions and have high mortality. Modifiable hospital practices around the escalation of care for these high-risk patients may contribute to poor outcomes. Earlier recognition of critical illness and timely ICU transfer may improve survival in hospitalized children with cancer.

A chemical synthesis of the D-ring of mersacidin is reported. The synthetic route relied upon development of a method for late-stage introduction of an unusual S-[(Z)-2-aminovinyl]-(3S)-3-methyl-d-cysteine (AviMeCys) functional group via an oxidative decarbonylation/decarboxylation reaction.

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The Pd- and Ni-promoted decarbonylation of amino acid thioesters proceeds smoothly to yield enamides. The synthesis of the (S)-(Z)-AviMeCys subunit of mersacidin, an MRSA-active lantibiotic, via this approach, is described.