Satoshi Omura’s research while affiliated with Kitasato University and other places

Anti-microbial resistance (AMR) is one of the greatest threats to global health. The continual battle between the emergence of AMR and the development of drugs will be extremely difficult to stop as long as traditional anti-biotic approaches are taken. In order to overcome this impasse, we here focused on the type III secretion system (T3SS), which is highly conserved in many Gram-negative pathogenic bacteria. The T3SS is known to be indispensable in establishing disease processes but not essential for pathogen survival. Therefore, T3SS inhibitors may be innovative anti-infective agents that could dramatically reduce the evolutionary selective pressure on strains resistant to treatment. Based on this concept, we previously identified a polyketide natural product, aurodox (AD), as a specific T3SS inhibitor using our original screening system. However, despite its promise as a unique anti-infective drug of AD, the molecular target of AD has remained unclear. In this paper, using an innovative chemistry and genetic biology-based approach, we show that AD binds to adenylosuccinate synthase (PurA), which suppresses the production of the secreted proteins from T3SS, resulting in the expression of bacterial virulence both in vitro and in vivo experiments. Our findings illuminate the potential of PurA as a target of anti-infective drugs and vaccination and could open a avenue for application of PurA in the regulation of T3SS.

Puberulic acid, a tropolone compound, has antibacterial and antimalarial activities. In this study, we investigated the in vitro inhibitory effects of puberulic acid on three Babesia species and Theileria equi. Puberulic acid inhibited the growth of Babesia bovis, Babesia bigemina, Babesia caballi, and Theileria equi with IC50 values of 1.79 ± 0.3, 1.58 ± 0.2, 2.6 ± 0.3, and 3.83 ± 0.4 µM, respectively, starting from an initial parasitemia of 1%. At 5 M, puberulic acid completely inhibited growth in B. caballi, 10 µM in B. bovis, and 25 µM in B. bigemina and T. equi cultures. Parasite growth was inhibited in the viability test at concentrations of 5 µM for B. bigemina and B. caballi, 10 µM for B. bovis, and 100 µM for T. equi. Puberulic acid had higher IC50 values than diminazene aceturate. At the concentrations used, the DMSO solvent did not influence the growth of the parasites. According to the in vitro results, puberulic acid may be a promising candidate for developing a new antibabesial drug. More research, including extensive in vivo assessment, is urgently needed.

The nitrogen rule in mass spectrometry was used to search for new nitrogen-compounds from microbial metabolites. During this program, two new nitrogen-containing compounds, penicidones E and F, were discovered from the filamentous fungal strain FKI-7498, which was isolated from soil collected in Tokushima, Japan and identified as Oidiodendron sp. by sequence analysis of the internal transcribed spacer region, including 5.8S ribosomal RNA. The structures of penicidones E and F were determined by mass spectrometry, nuclear magnetic resonance spectroscopy, and chemical modification analyses. These analyses revealed that penicidones E and F have a core structure of 3,5-dihydroxy-2-(4-pyridone-3-carbonyl)benzoic acid. Penicidone E exhibited hydroxyl radical scavenging activity.

Plasmodium falciparum contains several mitochondrial electron transport chain (ETC) dehydrogenases shuttling electrons from the respective substrates to the ubiquinone pool, from which electrons are consecutively transferred to complex III, complex IV, and finally to the molecular oxygen. The antimalarial drug atovaquone inhibits complex III and validates this parasite’s ETC as an attractive target for chemotherapy. Among the ETC dehydrogenases from P. falciparum, dihydroorotate dehydrogenase, an essential enzyme used in de novo pyrimidine biosynthesis, and complex III are the two enzymes that have been characterized and validated as drug targets in the blood-stage parasite, while complex II has been shown to be essential for parasite survival in the mosquito stage; therefore, these enzymes and complex II are considered candidate drug targets for blocking parasite transmission. In this study, we identified siccanin as the first (to our knowledge) nanomolar inhibitor of the P. falciparum complex II. Moreover, we demonstrated that siccanin also inhibits complex III in the low-micromolar range. Siccanin did not inhibit the corresponding complexes from mammalian mitochondria even at high concentrations. Siccanin inhibited the growth of P. falciparum with IC50 of 8.4 μM. However, the growth inhibition of the P. falciparum blood stage did not correlate with ETC inhibition, as demonstrated by lack of resistance to siccanin in the yDHODH-3D7 (EC50 = 10.26 μM) and Dd2-ELQ300 strains (EC50 = 18.70 μM), suggesting a third mechanism of action that is unrelated to mitochondrial ETC inhibition. Hence, siccanin has at least a dual mechanism of action, being the first potent and selective inhibitor of P. falciparum complexes II and III over mammalian enzymes and so is a potential candidate for the development of a new class of antimalarial drugs.

A p-quinone analog having the komaroviquinone pharmacophore fused with a more conformationally flexible cycloheptane ring, was semisynthesized from natural demethlsalvicanol isolated from Perovskia abrotanoides via four steps in 26% overall yield. The IC50 for the antitrypanosomal activity of the analog was 0.55 µM. Fullsize Image

Afidopyropen, a novel insecticide, is a derivative of pyripyropene A, which is produced by the filamentous fungus Penicillium coprobium. Afidopyropen has strong insecticidal activity against aphids and is currently used as a control agent of sucking pests worldwide. In this study, we summarized the biological properties and field efficacies of its derivatives against agricultural pests using official field trials conducted in Japan. Afidopyropen showed good residual efficacies against a variety of aphids, whiteflies and other sucking pests under field conditions. Furthermore, toxicological studies revealed its safety profiles against nontarget organisms, such as the honeybee, natural enemies and other beneficial insects, as well as mammals. Thus, afidopyropen is a next-generation agrochemical for crop protection that has a low environmental impact.

Trehangelins (THG) are newly identified trehalose compounds derived from broth cultures of an endophytic actinomycete, Polymorphospora rubra . THG are known to suppress Cellular Communication Network factor 1 (CCN1), which regulates collagen homeostasis in the dermis. Although the physical properties of THG suggest a high penetration of the stratum corneum, the effect of THG on the epidermis has not been reported. Here we describe a possible mechanism involved in skin aging focusing on the effect of THG on epidermal CCN1. This study shows that: (1) THG suppress epidermal CCN1 expression by inhibiting the translocation of Yes-Associated Protein (YAP) to nuclei. (2) Epidermal CCN1, localized at the basement membrane, regulates the balance between the growth and differentiation of keratinocytes. (3) Keratinocytes secrete more CCN1 than fibroblasts, which leads to disruption of the basement membrane and extracellular matrix components. (4) The secretion of CCN1 from keratinocytes is increased by ultraviolet B exposure, especially in aged keratinocytes, and deteriorates the elastic fiber structures in the underlying dermis. (5) Topical application of THG ameliorates the structure of the basement membrane in ex vivo human skin explants . Taken together, THG might be a promising treatment for aged skin by suppressing the aberrant YAP-CCN1 axis.

Actinobacteria are a group of ecologically important bacteria capable of producing diverse bioactive compounds. However, much remains unknown about the taxonomic and metabolic diversities of actinobacteria from many geographic regions and ecological niches. In this study, we report the isolation of actinobacteria from moss and moss-associated rhizosphere soils in Thailand. Among the 89 isolates analyzed for their bioactivities, 86 strains produced indole-3-acetic acid (IAA, ranging from 0.04 to 59.12 mg/L); 42 strains produced hydroxamate type of siderophore; 35 strains produced catecholate type of siderophore; 21 strains solubilized tricalcium phosphate; and many strains exhibited antagonistic activities against one to several of the seven selected plant, animal, and human pathogens. Overall, actinobacteria from the rhizosphere soil of mosses showed greater abilities to produce IAA and siderophores and to solubilize tricalcium phosphate than those from mosses. Among these 89 isolates, 37 were analyzed for their 16S rRNA gene sequences, which revealed their diverse phylogenetic distributions among seven genera, Streptomyces, Micromonospora, Nocardia, Actinoplanes, Saccharothrix, Streptosporangium, and Cryptosporangium. Furthermore, gas chromatography-mass spectrometry analyses of ethyl acetate crude extracts of three selected isolates with inhibitory effects against a methicillin-resistant Staphylococcus aureus strain revealed diverse metabolites with known antimicrobial activities. Together, our results demonstrate that actinobacteria from mosses in Thailand are taxonomically diverse and capable of producing a range of metabolites with plant-growth-promoting and microbial pathogen-inhibiting potentials.