Search

Our group previously identified MS-347a ( 1 ) as a new fungicide candidate from the culture broth of the mutant strain, Aspergillus sp. KTF-0058, which had the laeA gene inserted. This mutant strain was able to produce a sufficient supply of 1 , allowing for its use to investigate the structure-activity relationship. To this end, we synthesized 11 derivatives and evaluated their antifungal activity. Among these derivatives, the aldehyde derivative exhibited superior antifungal potency as compared to 1 , and some acyl derivatives were able to maintain the antifungal activity of 1 despite significant structural changes. From these results, it is found that the aldehyde derivative is one of the most promising fungicidal candidates, and the introduction of acyl groups could be utilized to create chemical probes for target-identification experiments., Competing Interests: Conflicts interestsThe authors declare no competing financial interest., (© 2024 Pesticide Science Society of Japan.)

An antifungal polyene-decalin polyketide natural product, burnettiene A ( 1 ) has been re-discovered from the culture broth of Lecanicillium primulinum (current name: Flavocillium primulinum ) FKI-6715 strain utilizing our original multidrug-sensitive yeast system. This polyene-decalin polyketide natural product was originally isolated from Aspergillus burnettii . The antifungal activity of 1 against Candida albicans has been reported. However, only one fungal species for the antifungal activity of 1 has been revealed, and details of the antifungal activity against other pathogenic fungus remain unknown. After extensive screening for antifungal activity, we found that 1 exhibits broad antifungal activity against pathogenic plant fungi, including Colletotrichum gloeosporioides , Botrytis cinerea , Pyricularia oryzae , Leptosphaeria maculans , and Rhizoctonia solani . Furthermore, we synthesized 12 derivatives from 1 and evaluated their antifungal activity to reveal the detailed structure-activity relationship. The methyl ester derivative showed antifungal activity against Saccharomyces cerevisiae 12geneΔ0HSR-iERG6 100-fold more potent than that of 1 . Our research indicates that 1 would be a promising natural product as a new fungicidal candidate and the methyl ester derivative especially has great potential., (© 2024 Pesticide Science Society of Japan.)

KSP-1007 is a novel bicyclic boronate-based broad-spectrum β-lactamase inhibitor and is being developed in combination with meropenem (MEM) for the treatment of infections caused by carbapenem-resistant Gram-negative bacteria, a global health concern, and here, we describe its characteristics. KSP-1007 exhibited low apparent inhibition constant ( K i app ) values against all classes of β-lactamase, including imipenemase types and oxacillinase types from Acinetobacter baumannii . Against 207 Enterobacterales and 55 A . baumannii , including carbapenemase producers, KSP-1007 at fixed concentrations of 4, 8, and 16 µg/mL dose-dependently potentiated the in vitro activity of MEM in broth microdilution MIC testing. The MIC 90 of MEM/KSP-1007 at 8 µg/mL against Enterobacterales was lower than those of MEM/vaborbactam, ceftazidime/avibactam, imipenem/relebactam, and colistin and similar to those of aztreonam/avibactam, cefiderocol, and tigecycline. The in vitro activity of MEM/KSP-1007 at ≥4 µg/mL against Enterobacterales harboring metallo-β-lactamase was superior to that of cefepime/taniborbactam. MEM/KSP-1007 showed excellent activity against Escherichia coli with PBP3 mutations and New Delhi metallo-β-lactamase compared to aztreonam/avibactam, cefepime/taniborbactam, and cefiderocol. MEM/KSP-1007 at 8 µg/mL showed greater efficacy against A. baumannii than these comparators except for cefiderocol, tigecycline, and colistin. A 2-fold reduction in MEM MIC against 96 Pseudomonas aeruginosa was observed in combination with KSP-1007. MEM/KSP-1007 demonstrated bactericidal activity against carbapenemase-producing Enterobacterales , A. baumannii , and P. aeruginosa based on minimum bactericidal concentration/MIC ratios of ≤4. KSP-1007 enhanced the in vivo activity of MEM against carbapenemase-producing Enterobacterales , A. baumannii , and P. aeruginosa in murine systemic, complicated urinary tract, and thigh infection models. Collectively, MEM/KSP-1007 has a good profile for treating carbapenem-resistant Gram-negative bacterial infections., Competing Interests: K.T., R.N., K.F., S.K., and J.H. are employees of Sumitomo Pharma Co., Ltd. K.F. and J.H. own stock options in the company. K.T., R.N., and S.K. hold no stock options in the company.

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., Competing Interests: Competing interests statement:The authors declare no competing interest.

Six aromatic secondary metabolites, pestalone (1), emodin (2), phomopsilactone (3), pestalachlorides B (4), C (5), and D (6), were isolated from Pestalotiopsis sp. FKR-0115, a filamentous fungus collected from white moulds growing on dead branches in Minami Daito Island. The efficacy of these secondary metabolites against methicillin-resistant Staphylococcus aureus (MRSA) with and without meropenem (β-lactam antibiotic) was evaluated using the paper disc method and broth microdilution method. The chemical structures of the isolated compounds (1-6) were characterised using spectroscopic methods, including nuclear magnetic resonance and mass spectrometry. All six isolated compounds exhibited synergistic activity with meropenem against MRSA. Among the six secondary metabolites, pestalone (1) overcame bacterial resistance in MRSA to the greatest extent.

We previously identified a new heparinase inhibitor fungal metabolite, named CRM646-A, which showed inhibition of heparinase and telomerase activities in an in vitro enzyme assay and antimetastatic activity in a cell-based assay. In this study, we elucidated the mechanism by which CRM646-A rapidly induced nucleus condensation, plasma membrane disruption and morphological changes by increasing intracellular Ca 2+ levels. Furthermore, PD98059, a mitogen-activated protein kinase (MEK) inhibitor, inhibited CRM646-A-induced nucleus condensation through ERK1/2 activation in rat 3Y1 fibroblast cells. We identified CRM646-A as a Ca 2+ ionophore-like agent with a distinctly different chemical structure from that of previously reported Ca 2+ ionophores. These results indicate that CRM646-A has the potential to be used as a new and effective antimetastatic drug.