Hepatic safety and tolerability of cipargamin (KAE609), in adult patients with Plasmodium falciparum malaria: a randomized, phase II, controlled, dose-escalation trial in sub-Saharan Africa.

Background: The novel anti-malarial cipargamin (KAE609) has potent, rapid activity against Plasmodium falciparum. Transient asymptomatic liver function test elevations were previously observed in cipargamin-treated subjects in two trials: one in malaria patients in Asia and one in volunteers with experimentally induced malaria. In this study, the hepatic safety of cipargamin given as single doses of 10 to 150 mg and 10 to 50 mg once daily for 3 days was assessed.

Efficacy of Cipargamin (KAE609) in a Randomized, Phase II Dose-Escalation Study in Adults in Sub-Saharan Africa With Uncomplicated Plasmodium falciparum Malaria.

Background: Cipargamin (KAE609) is a potent antimalarial in a phase II trial. Here we report efficacy, pharmacokinetics, and resistance marker analysis across a range of cipargamin doses. These were secondary endpoints from a study primarily conducted to assess the hepatic safety of cipargamin (hepatic safety data are reported elsewhere).

High Prevalence of Plasmodium falciparum K13 Mutations in Rwanda Is Associated With Slow Parasite Clearance After Treatment With Artemether-Lumefantrine.

In Southeast Asia, mutations in the Plasmodium falciparum K13 gene have led to delayed parasite clearance and treatment failures in patients with malaria receiving artemisinin combination therapies. Until recently, relevant K13 mutations had been mostly absent from Africa. Between 2018 and 2019, a phase 2 clinical study with 186 patients was conducted in Mali, Gabon, Ghana, Uganda, and Rwanda.

The early preclinical and clinical development of cipargamin (KAE609), a novel antimalarial compound.

Background: Cipargamin (KAE609) is a novel spiroindolone class drug for the treatment of malaria, currently undergoing phase 2 clinical development. This review provides an overview and interpretation of the pre-clinical and clinical data of this possible next-generation antimalarial drug published to date.

Methods: We systematically searched the literature for studies on the preclinical and clinical development of cipargamin.

Indoleacrylic Acid Produced by Commensal Peptostreptococcus Species Suppresses Inflammation.

Host factors in the intestine help select for bacteria that promote health. Certain commensals can utilize mucins as an energy source, thus promoting their colonization. However, health conditions such as inflammatory bowel disease (IBD) are associated with a reduced mucus layer, potentially leading to dysbiosis associated with this disease.

Gift from Nature: Cyclomarin A Kills Mycobacteria and Malaria Parasites by Distinct Modes of Action.

Malaria continues to be one of the most devastating human diseases despite many efforts to limit its spread by prevention of infection or by pharmaceutical treatment of patients. We have conducted a screen for antiplasmodial compounds by using a natural product library. Here we report on cyclomarin A as a potent growth inhibitor of Plasmodium falciparum and the identification of its molecular target, diadenosine triphosphate hydrolase (PfAp3Aase), by chemical proteomics.

Natural products as probes in pharmaceutical research.

From the start of the pharmaceutical research natural products played a key role in drug discovery and development. Over time many discoveries of fundamental new biology were triggered by the unique biological activity of natural products. Unprecedented chemical structures, novel chemotypes, often pave the way to investigate new biology and to explore new pathways and targets.

Luteipulveratus halotolerans sp. nov., an actinobacterium (Dermacoccaceae) from forest soil.

The taxonomic position of an actinobacterium strain, C296001T, isolated from a soil sample collected in Sarawak, Malaysia, was established using a polyphasic approach. Phylogenetically, strain C296001T was closely associated with the genus Luteipulveratus and formed a distinct monophyletic clade with the only described species, Luteipulveratus mongoliensis NBRC 105296T. The 16S rRNA gene sequence similarity between strain C296001T and L.

Nannocystin A: an Elongation Factor 1 Inhibitor from Myxobacteria with Differential Anti-Cancer Properties.

Cultivation of myxobacteria of the Nannocystis genus led to the isolation and structure elucidation of a class of novel cyclic lactone inhibitors of elongation factor 1. Whole genome sequence analysis and annotation enabled identification of the putative biosynthetic cluster and synthesis process. In biological assays the compounds displayed anti-fungal and cytotoxic activity.

The novolactone natural product disrupts the allosteric regulation of Hsp70.

The highly conserved 70 kDa heat shock proteins (Hsp70) play an integral role in proteostasis such that dysregulation has been implicated in numerous diseases. Elucidating the precise role of Hsp70 family members in the cellular context, however, has been hampered by the redundancy and intricate regulation of the chaperone network, and relatively few selective and potent tools. We have characterized a natural product, novolactone, that targets cytosolic and ER-localized isoforms of Hsp70 through a highly conserved covalent interaction at the interface between the substrate-binding and ATPase domains.

Selective and specific inhibition of the plasmodium falciparum lysyl-tRNA synthetase by the fungal secondary metabolite cladosporin.

With renewed calls for malaria eradication, next-generation antimalarials need be active against drug-resistant parasites and efficacious against both liver- and blood-stage infections. We screened a natural product library to identify inhibitors of Plasmodium falciparum blood- and liver-stage proliferation. Cladosporin, a fungal secondary metabolite whose target and mechanism of action are not known for any species, was identified as having potent, nanomolar, antiparasitic activity against both blood and liver stages.

Natural products as catalysts for innovation: a pharmaceutical industry perspective.

Natural products are evolutionarily designed and chemically distinct from most synthetic library molecules. In addition to their role as drugs, they are successfully used as molecular probes to identify disease relevant targets. Novel natural products are still routinely discovered from traditional sources through cultivation of microorganisms.

Spiroindolones, a potent compound class for the treatment of malaria.

Recent reports of increased tolerance to artemisinin derivatives--the most recently adopted class of antimalarials--have prompted a need for new treatments. The spirotetrahydro-beta-carbolines, or spiroindolones, are potent drugs that kill the blood stages of Plasmodium falciparum and Plasmodium vivax clinical isolates at low nanomolar concentration. Spiroindolones rapidly inhibit protein synthesis in P.

Spirotetrahydro beta-carbolines (spiroindolones): a new class of potent and orally efficacious compounds for the treatment of malaria.

The antiplasmodial activity of a series of spirotetrahydro beta-carbolines is described. Racemic spiroazepineindole (1) was identified from a phenotypic screen on wild type Plasmodium falciparum with an in vitro IC(50) of 90 nM. Structure-activity relationships for the optimization of 1 to compound 20a (IC(50) = 0.

Small molecule inhibitors of Wnt/beta-catenin/lef-1 signaling induces apoptosis in chronic lymphocytic leukemia cells in vitro and in vivo.

Background: Lymphoid enhancer factor-1 (lef-1) is overexpressed in B-cell chronic lymphocytic leukemia (CLL) when compared with normal B cells and transcribes several genes implicated in the pathogenesis of CLL. We therefore hypothesize that antagonism of lef-1 might lead to killing of CLL cells. We used two small molecule inhibitors of Wnt/beta-catenin/lef-1 signaling (CGP049090 and PKF115-584) to test our hypothesis.

Ribosomally synthesized thiopeptide antibiotics targeting elongation factor Tu.

We identified the thiomuracins, a novel family of thiopeptides produced by a rare-actinomycete bacterium typed as a Nonomuraea species, via a screen for inhibition of growth of the bacterial pathogen Staphylococcus aureus. Thiopeptides are a class of macrocyclic, highly modified peptides that are decorated by thiazoles and defined by a central six-membered heterocyclic ring system. Mining the genomes of thiopeptide-producing strains revealed the elusive biosynthetic route for this class of antibiotics.

Small molecule inhibitors of WNT signaling effectively induce apoptosis in acute myeloid leukemia cells.

In a significant proportion of acute myeloid leukemia (AML) cases the canonical WNT pathway is upregulated and targeting the WNT/LEF1 signaling cascade in AML may be a promising approach to develop new treatments for this entity. Recently two compounds (CGP049090 and PFK115-584) have been identified, which specifically inhibit complexation of beta-catenin (CTNNB1) and lymphoid enhancer-binding factor 1 (LEF1) leading to transcriptional inactivation of LEF1 in colon carcinoma cell lines. To evaluate the effect of WNT inhibition utilizing theses compounds with regard to their effectivity in AML we treated the AML cell lines Kasumi-1 and HL-60, primary AML blasts and healthy peripheral blood mononuclear cells (PBMCs) with varying concentrations of both substances.

Lipiarmycin targets RNA polymerase and has good activity against multidrug-resistant strains of Mycobacterium tuberculosis.

Objectives: The aim of this study was to determine the in vitro activity of lipiarmycin against drug-resistant strains of Mycobacterium tuberculosis (MTB) and to establish the resistance mechanism of MTB against lipiarmycin using genetic approaches.

Methods: MIC values were measured against a panel of drug-resistant strains of MTB using the broth microdilution method. Spontaneous lipiarmycin-resistant mutants of MTB were tested for cross-resistance to standard anti-TB drugs, and their rpoB and rpoC genes were sequenced to identify mutations.

Recent developments in antibacterial drug discovery: microbe-derived natural products--from collection to the clinic.

The pharmaceutical industry has historically relied on nature to provide compounds for antibacterial drug discovery. In recent years, several pharmaceutical companies have scaled back their efforts in natural product research. Nevertheless, the screening of natural products for antibacterial activity continues to provide excellent sources of biologically and chemically informative leads for new drugs.

CPCR1, but not its interacting transcription factor AcFKH1, controls fungal arthrospore formation in Acremonium chrysogenum.

Fungal morphogenesis and secondary metabolism are frequently associated; however, the molecular determinants connecting both processes remain largely undefined. Here we demonstrate that CPCR1 (cephalosporin C regulator 1 from Acremonium chrysogenum), a member of the winged helix/regulator factor X (RFX) transcription factor family that regulates cephalosporin C biosynthesis, also controls morphological development in the beta-lactam producer A. chrysogenum.