Pub Date : 2025-05-16DOI: 10.1038/s41429-025-00828-5
Hiroyasu Onaka
Actinomycetes, particularly Streptomyces, are soil microorganisms that produce diverse secondary metabolites with pharmaceutical applications, such as antibiotics and anticancer drugs. These metabolites play important roles in microbial competition and survival. This review highlights three major aspects of actinomycete secondary metabolism: (1) the biosynthesis of indolocarbazoles, (2) the biosynthesis of RiPPs (ribosomally synthesized and post-translationally modified peptides), and (3) the activation of secondary metabolism through microbial interactions. Indolocarbazoles, including staurosporine and rebeccamycin, are potent inhibitors of kinases and DNA topoisomerase I, with potential as anticancer agents. Their biosynthetic pathways involve multiple enzymatic steps, notably carbon–carbon bond formation catalyzed by cytochrome P450 enzymes. RiPPs such as goadsporin and lactazole are highly modular peptide natural products; structural gene modification enables the generation of diverse analogs. A cell-free one-pot synthesis platform has been developed for efficient analog production. To activate cryptic biosynthetic pathways, we employed a combined-culture strategy using actinomycetes and mycolic acid-containing bacteria, resulting in the discovery of 42 novel compounds. Genetic and physiological data indicate that physical contact, rather than diffusible signaling, is essential for induction. These insights emphasize the importance of microbial interactions in natural product biosynthesis and offer new directions for drug discovery through synthetic biology and microbial ecology.
{"title":"Unlocking hidden bioactive compounds: from indolocarbazole and RiPP biosynthesis to the activation of cryptic secondary metabolism via microbial interactions","authors":"Hiroyasu Onaka","doi":"10.1038/s41429-025-00828-5","DOIUrl":"10.1038/s41429-025-00828-5","url":null,"abstract":"Actinomycetes, particularly Streptomyces, are soil microorganisms that produce diverse secondary metabolites with pharmaceutical applications, such as antibiotics and anticancer drugs. These metabolites play important roles in microbial competition and survival. This review highlights three major aspects of actinomycete secondary metabolism: (1) the biosynthesis of indolocarbazoles, (2) the biosynthesis of RiPPs (ribosomally synthesized and post-translationally modified peptides), and (3) the activation of secondary metabolism through microbial interactions. Indolocarbazoles, including staurosporine and rebeccamycin, are potent inhibitors of kinases and DNA topoisomerase I, with potential as anticancer agents. Their biosynthetic pathways involve multiple enzymatic steps, notably carbon–carbon bond formation catalyzed by cytochrome P450 enzymes. RiPPs such as goadsporin and lactazole are highly modular peptide natural products; structural gene modification enables the generation of diverse analogs. A cell-free one-pot synthesis platform has been developed for efficient analog production. To activate cryptic biosynthetic pathways, we employed a combined-culture strategy using actinomycetes and mycolic acid-containing bacteria, resulting in the discovery of 42 novel compounds. Genetic and physiological data indicate that physical contact, rather than diffusible signaling, is essential for induction. These insights emphasize the importance of microbial interactions in natural product biosynthesis and offer new directions for drug discovery through synthetic biology and microbial ecology.","PeriodicalId":54884,"journal":{"name":"Journal of Antibiotics","volume":"78 7","pages":"395-407"},"PeriodicalIF":2.7,"publicationDate":"2025-05-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144086986","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-05-15DOI: 10.1038/s41429-025-00829-4
Dong Kwon, Nadarajah Vasanthan, Noor Ibrahim, Noel Yahra
Gram-negative bacterial pathogens are responsible for various infections. Over the past decade, these pathogens have acquired resistance to multiple antibiotics, and the multidrug-resistant (MDR) bacteria have rapidly spread globally, creating significant treatment challenges. Quaternized cellulose nanocrystals (CNCs) have promising antibacterial properties. We previously reported quaternized CNCs with ten-carbon (CNC-3) and sixteen-carbon (CNC-4) alkyl chains and an unmodified CNC (CNC-1). We found that CNC-4 exhibited a significant bactericidal effect against Staphylococcus aureus. In this study, we aim to evaluate the antibacterial properties of the quaternized CNCs against Gram-negative MDR clinical isolates of Acinetobacter baumannii (21 isolates), Klebsiella pneumoniae (18 isolates), and Escherichia coli (7 isolates), including each of their reference species. Agar diffusion, minimum bactericidal concentration (MBC), and bacterial killing pattern were conducted. The results showed that CNC-3 exhibited an MBC of 50 μg ml−1 for 28% (13 out of 46 isolates) and 100 μg ml−1 for 72% (33 out of 46 isolates), regardless of their antibiotic susceptibility. In comparison, CNC-4 exhibited an MBC of 100 μg ml−1 for 28% (5 out of 18 K. pneumoniae), while all other isolates and the reference species exhibited an MBC of >100 μg ml−1. For CNC-1, the MBC was >100 μg ml−1 for all tested isolates and the reference species. These results suggest that, unlike S. aureus, CNC-3 has a significantly higher and broader spectrum of bactericidal effects than CNC-4 against Gram-negative bacteria. This finding suggests that quaternized CNCs may be a potential antimicrobial agent for treating Gram-negative bacterial infections.
{"title":"Antibacterial properties of quaternized cellulose nanocrystals in clinical isolates of multidrug-resistant gram-negative bacteria","authors":"Dong Kwon, Nadarajah Vasanthan, Noor Ibrahim, Noel Yahra","doi":"10.1038/s41429-025-00829-4","DOIUrl":"10.1038/s41429-025-00829-4","url":null,"abstract":"Gram-negative bacterial pathogens are responsible for various infections. Over the past decade, these pathogens have acquired resistance to multiple antibiotics, and the multidrug-resistant (MDR) bacteria have rapidly spread globally, creating significant treatment challenges. Quaternized cellulose nanocrystals (CNCs) have promising antibacterial properties. We previously reported quaternized CNCs with ten-carbon (CNC-3) and sixteen-carbon (CNC-4) alkyl chains and an unmodified CNC (CNC-1). We found that CNC-4 exhibited a significant bactericidal effect against Staphylococcus aureus. In this study, we aim to evaluate the antibacterial properties of the quaternized CNCs against Gram-negative MDR clinical isolates of Acinetobacter baumannii (21 isolates), Klebsiella pneumoniae (18 isolates), and Escherichia coli (7 isolates), including each of their reference species. Agar diffusion, minimum bactericidal concentration (MBC), and bacterial killing pattern were conducted. The results showed that CNC-3 exhibited an MBC of 50 μg ml−1 for 28% (13 out of 46 isolates) and 100 μg ml−1 for 72% (33 out of 46 isolates), regardless of their antibiotic susceptibility. In comparison, CNC-4 exhibited an MBC of 100 μg ml−1 for 28% (5 out of 18 K. pneumoniae), while all other isolates and the reference species exhibited an MBC of >100 μg ml−1. For CNC-1, the MBC was >100 μg ml−1 for all tested isolates and the reference species. These results suggest that, unlike S. aureus, CNC-3 has a significantly higher and broader spectrum of bactericidal effects than CNC-4 against Gram-negative bacteria. This finding suggests that quaternized CNCs may be a potential antimicrobial agent for treating Gram-negative bacterial infections.","PeriodicalId":54884,"journal":{"name":"Journal of Antibiotics","volume":"78 7","pages":"442-448"},"PeriodicalIF":2.7,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144081752","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Contezolid, a novel oxazolidinone antibiotic, has comparable or superior antibacterial efficacy and safety to linezolid, now widely used for treating multidrug-resistant Gram-positive bacterial infections. Although numerous studies have investigated the immunomodulatory effects of oxazolidinone antibiotics, the immunomodulatory properties of contezolid remain poorly understood. This study aimed to investigate the anti‑inflammatory effects of contezolid using LPS-stimulated RAW264.7 macrophages. Experimental assessments demonstrated that contezolid significantly suppressed key inflammatory mediators, including nitric oxide and reactive oxygen species, while reducing IL-6 and TNF-α cytokine levels and CD86 concurrently. Functional analysis revealed attenuated phagocytic activity through fluorescence-based bacterial internalization assays and viable bacterial colony counting. Mechanistic studies using qRT-PCR identified transcriptional downregulation of Toll-like receptors, with TLR2 showing particularly pronounced suppression compared to activated controls. These findings indicate that, in addition to its known antimicrobial activity, contezolid also exhibits anti-inflammatory properties.
{"title":"Contezolid, a novel oxazolidinone antibiotic, acts as a potential anti-inflammatory agent","authors":"Lu Liu, Junsheng Chen, Yajie Deng, Fei Gao, Ting Lin, Zhijun Yang, Daijie Chen, Yu Yin","doi":"10.1038/s41429-025-00825-8","DOIUrl":"10.1038/s41429-025-00825-8","url":null,"abstract":"Contezolid, a novel oxazolidinone antibiotic, has comparable or superior antibacterial efficacy and safety to linezolid, now widely used for treating multidrug-resistant Gram-positive bacterial infections. Although numerous studies have investigated the immunomodulatory effects of oxazolidinone antibiotics, the immunomodulatory properties of contezolid remain poorly understood. This study aimed to investigate the anti‑inflammatory effects of contezolid using LPS-stimulated RAW264.7 macrophages. Experimental assessments demonstrated that contezolid significantly suppressed key inflammatory mediators, including nitric oxide and reactive oxygen species, while reducing IL-6 and TNF-α cytokine levels and CD86 concurrently. Functional analysis revealed attenuated phagocytic activity through fluorescence-based bacterial internalization assays and viable bacterial colony counting. Mechanistic studies using qRT-PCR identified transcriptional downregulation of Toll-like receptors, with TLR2 showing particularly pronounced suppression compared to activated controls. These findings indicate that, in addition to its known antimicrobial activity, contezolid also exhibits anti-inflammatory properties.","PeriodicalId":54884,"journal":{"name":"Journal of Antibiotics","volume":"78 6","pages":"384-387"},"PeriodicalIF":2.7,"publicationDate":"2025-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144019270","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-05-07DOI: 10.1038/s41429-025-00823-w
Bekir Özer, Emel Mataraci Kara, Berna Özbek Çelik
This study examines the effects of combining eravacycline with various antibiotics on carbapenem-resistant Enterobacterales (CRE) isolated from bloodstream infections. Fifty Enterobacterales isolates that produce the OXA-48 enzyme were tested for their Minimum Inhibitory Concentrations (MICs) using broth microdilution. The Mutant Prevention Concentrations (MPCs) of eravacycline, tigecycline, levofloxacin, colistin, fosfomycin, meropenem, and tobramycin were evaluated against CRE isolates. The bactericidal and synergistic effects of eravacycline, alone or in combination with other antibiotics, were assessed using time-kill curve (TKC) experiments. The in vitro synergistic activities of tested antibiotics in combination with eravacycline were also determined by microbroth checkerboard technique, and results were interpreted using the fractional inhibitory concentration (FIC) index. The results of our study demonstrated that colistin exhibited the best bactericidal activity and the highest susceptibility rates among the evaluated strains. Eravacycline exhibited lower MPC values compared to tigecycline when used alone. The results of the TCK method showed that the most effective synergistic interactions were observed when eravacycline was combined with levofloxacin, colistin, or meropenem. The results obtained by microbroth checkerboard techniques also described synergistic activity with all tested eravacycline combinations against tested clinical isolates of Enterobacterales. No antagonism was detected. The study’s results indicate that the combination of eravacycline with colistin, meropenem, tobramycin or levofloxacin showed synergistic activity against strains of Enterobacterales that produce OXA-48. This combination therapy may be a viable alternative for treating carbapenemase-producing Enterobacterales bacteria. In addition, eravacycline’s lower MPC value suggests it may avoid the emergence of resistant mutant strains in the population.
{"title":"In vitro synergistic effect and mutant prevention concentration of eravacycline alone or in combination with various antibiotics against OXA-48 producing enterobacterales","authors":"Bekir Özer, Emel Mataraci Kara, Berna Özbek Çelik","doi":"10.1038/s41429-025-00823-w","DOIUrl":"10.1038/s41429-025-00823-w","url":null,"abstract":"This study examines the effects of combining eravacycline with various antibiotics on carbapenem-resistant Enterobacterales (CRE) isolated from bloodstream infections. Fifty Enterobacterales isolates that produce the OXA-48 enzyme were tested for their Minimum Inhibitory Concentrations (MICs) using broth microdilution. The Mutant Prevention Concentrations (MPCs) of eravacycline, tigecycline, levofloxacin, colistin, fosfomycin, meropenem, and tobramycin were evaluated against CRE isolates. The bactericidal and synergistic effects of eravacycline, alone or in combination with other antibiotics, were assessed using time-kill curve (TKC) experiments. The in vitro synergistic activities of tested antibiotics in combination with eravacycline were also determined by microbroth checkerboard technique, and results were interpreted using the fractional inhibitory concentration (FIC) index. The results of our study demonstrated that colistin exhibited the best bactericidal activity and the highest susceptibility rates among the evaluated strains. Eravacycline exhibited lower MPC values compared to tigecycline when used alone. The results of the TCK method showed that the most effective synergistic interactions were observed when eravacycline was combined with levofloxacin, colistin, or meropenem. The results obtained by microbroth checkerboard techniques also described synergistic activity with all tested eravacycline combinations against tested clinical isolates of Enterobacterales. No antagonism was detected. The study’s results indicate that the combination of eravacycline with colistin, meropenem, tobramycin or levofloxacin showed synergistic activity against strains of Enterobacterales that produce OXA-48. This combination therapy may be a viable alternative for treating carbapenemase-producing Enterobacterales bacteria. In addition, eravacycline’s lower MPC value suggests it may avoid the emergence of resistant mutant strains in the population.","PeriodicalId":54884,"journal":{"name":"Journal of Antibiotics","volume":"78 6","pages":"370-379"},"PeriodicalIF":2.7,"publicationDate":"2025-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144052952","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Lascufloxacin (LSFX) achieves concentrations in epithelial lining fluid (ELF) that are more than 15 times higher than those in the bloodstream, making it a promising candidate for respiratory and otorhinolaryngological infections. These concentrations were replicated using the Hollow-Fiber Infection Model and demonstrated bactericidal efficacy of LSFX against levofloxacin-sensitive and -resistant Streptococcus pneumoniae. The study confirms that LSFX’s elevated concentration in ELF plays a significant role in its bactericidal activity.
{"title":"Evaluation of lung epithelial lining fluid concentrations of lascufloxacin against Streptococcus pneumoniae in a hollow-fiber infection model","authors":"Haruka Nakagawa Kamura, Tetsuo Yamaguchi, Toshihiro Kasama, Yukitaka Hayashi, Masakaze Hamada, Kazuaki Matsumoto, Ryo Miyake, Yoshikazu Ishii","doi":"10.1038/s41429-025-00826-7","DOIUrl":"10.1038/s41429-025-00826-7","url":null,"abstract":"Lascufloxacin (LSFX) achieves concentrations in epithelial lining fluid (ELF) that are more than 15 times higher than those in the bloodstream, making it a promising candidate for respiratory and otorhinolaryngological infections. These concentrations were replicated using the Hollow-Fiber Infection Model and demonstrated bactericidal efficacy of LSFX against levofloxacin-sensitive and -resistant Streptococcus pneumoniae. The study confirms that LSFX’s elevated concentration in ELF plays a significant role in its bactericidal activity.","PeriodicalId":54884,"journal":{"name":"Journal of Antibiotics","volume":"78 6","pages":"388-391"},"PeriodicalIF":2.7,"publicationDate":"2025-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12106058/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144060261","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-04-24DOI: 10.1038/s41429-025-00824-9
Dae-Cheol Choi, Dae-Won Ki, Yoon Hee Kim, Min-Ju Park, Ji-Yul Kim, In-Kyoung Lee, Bong-Sik Yun
A new dimeric 5-hydroxy-2-hexenoic acid, clonohexenoic acid (1), a known 14-membered macrolide, acremodiol B (2), and two known benzochromenone derivatives, alternariol (3) and 2-hydroxyalternariol (4), were isolated from a culture broth of Clonostachys rogersoniana. The structures of these isolated compounds were determined using spectroscopic methods. Antimicrobial and cytotoxic activities of these compounds were then assessed. Compounds 1‒4 exhibited antimicrobial activities against Bacillus subtilis and Propionibacterium acnes. In addition, compounds 3 and 4 showed antibacterial activities against B. cereus and cytotoxic activities against three human cancer cell lines, A549, HCT-116, and Mia Paca-2.
{"title":"New dimeric 5-hydroxy-2-hexenoic acid isolated from culture broth of Clonostachys rogersoniana","authors":"Dae-Cheol Choi, Dae-Won Ki, Yoon Hee Kim, Min-Ju Park, Ji-Yul Kim, In-Kyoung Lee, Bong-Sik Yun","doi":"10.1038/s41429-025-00824-9","DOIUrl":"10.1038/s41429-025-00824-9","url":null,"abstract":"A new dimeric 5-hydroxy-2-hexenoic acid, clonohexenoic acid (1), a known 14-membered macrolide, acremodiol B (2), and two known benzochromenone derivatives, alternariol (3) and 2-hydroxyalternariol (4), were isolated from a culture broth of Clonostachys rogersoniana. The structures of these isolated compounds were determined using spectroscopic methods. Antimicrobial and cytotoxic activities of these compounds were then assessed. Compounds 1‒4 exhibited antimicrobial activities against Bacillus subtilis and Propionibacterium acnes. In addition, compounds 3 and 4 showed antibacterial activities against B. cereus and cytotoxic activities against three human cancer cell lines, A549, HCT-116, and Mia Paca-2.","PeriodicalId":54884,"journal":{"name":"Journal of Antibiotics","volume":"78 6","pages":"380-383"},"PeriodicalIF":2.7,"publicationDate":"2025-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144043185","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
The escalating antibiotic resistance presents formidable challenges in the treatment of Gram-negative bacterial infections. Clinically, these bacteria have also acquired resistance to polymyxin, the last resort of defense. Novel antibiotics with a single mode of action are susceptible to rapid resistance development, and sometimes asynchronous pharmacokinetics also hinders the effectiveness of combined administration strategies in vivo. Here, we developed a class of novel bifunctional antibacterial peptides by covalently conjugating a series of modified PbgA-derived peptides with colistin analog (PE-2C-C8-DH) via a small-molecule linker (KCM02). These bifunctional peptides show remarkable synergistic antibacterial efficacy, where “1 + 1 > 2”, against various priority multidrug-resistant Gram-negative bacteria, involving polymyxin-resistant strains. By optimizing the structure-activity relationship, two compounds (BP-28 and BP-37) with distinct activity preferences were obtained, which possess rapid bactericidal efficacy and a significantly lower risk of resistance compared to single-mode-of-action antibacterial agents, without hemolytic toxicity and cytotoxicity. Identification of antibacterial targets revealed that they can damage Gram-negative bacterial membrane by targeting LPS and BamA. Our study offers a referable approach for the development of novel antimicrobial agents.
{"title":"Novel bifunctional antibacterial peptides mediated by a covalent conjugation strategy combat priority multidrug-resistant gram-negative pathogens through dual targets","authors":"Yanan Li, Haoran Mei, Yuanzhen Dong, Jianguang Lu, Xiaoqian Yang, Ying Zhang, Meiqing Feng, Jun Feng","doi":"10.1038/s41429-025-00822-x","DOIUrl":"10.1038/s41429-025-00822-x","url":null,"abstract":"The escalating antibiotic resistance presents formidable challenges in the treatment of Gram-negative bacterial infections. Clinically, these bacteria have also acquired resistance to polymyxin, the last resort of defense. Novel antibiotics with a single mode of action are susceptible to rapid resistance development, and sometimes asynchronous pharmacokinetics also hinders the effectiveness of combined administration strategies in vivo. Here, we developed a class of novel bifunctional antibacterial peptides by covalently conjugating a series of modified PbgA-derived peptides with colistin analog (PE-2C-C8-DH) via a small-molecule linker (KCM02). These bifunctional peptides show remarkable synergistic antibacterial efficacy, where “1 + 1 > 2”, against various priority multidrug-resistant Gram-negative bacteria, involving polymyxin-resistant strains. By optimizing the structure-activity relationship, two compounds (BP-28 and BP-37) with distinct activity preferences were obtained, which possess rapid bactericidal efficacy and a significantly lower risk of resistance compared to single-mode-of-action antibacterial agents, without hemolytic toxicity and cytotoxicity. Identification of antibacterial targets revealed that they can damage Gram-negative bacterial membrane by targeting LPS and BamA. Our study offers a referable approach for the development of novel antimicrobial agents.","PeriodicalId":54884,"journal":{"name":"Journal of Antibiotics","volume":"78 6","pages":"359-369"},"PeriodicalIF":2.7,"publicationDate":"2025-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144034952","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
The combined-culture of actinomycetes with mycolic acid-containing bacteria (MACB) Tsukamurella pulmonis TP-B0596 is a promising strategy to produce cryptic metabolites in actinomycetes. In this study, Streptomyces sp. 23-50 was identified as an appropriate strain for co-culturing with T. pulmonis TP-B0596 using on-gel combined-culture screening of 160 strains of actinomycetes. A new pyranonaphthoquinone, actinoquinonal A (1), along with two known congeners, compound 2 and mevashuntin (3), were isolated from the combined-culture of Streptomyces sp. 23-50 with T. pulmonis TP-B0596 based on global natural product social (GNPS) molecular networking. The planar structures of 1–3 were elucidated by analyzing 2D nuclear magnetic resonance (NMR) and LC-MS/MS spectral data, and the absolute configurations of 1 and 3 were unambiguously determined by comparing experimental and calculated ECD spectra. Moreover, the combined-culture characteristic metabolites, including 3, were enhanced when Streptomyces sp. 23-50 was cultured in the presence of pravastatin, an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase in the mevalonate pathway, suggesting that T. pulmonis TP-B0596 triggered a shunt in the mevalonate pathway of Streptomyces sp. 23-50. Notably, compounds 1 and 3 exhibited cytotoxicity against human cervical epithelioid carcinoma HeLa S3 (IC50 = 60.5 μM for 1, 0.67 μM for 3) and human colorectal cancer HT29 cells (IC50 = 101.9 μM for 1, 0.45 μM for 3).
{"title":"A new pyranonaphthoquinone, actinoquinonal A, and its congeners from the combined-culture of Streptomyces sp. 23–50 and Tsukamurella pulmonis TP-B0596","authors":"Kazuki Yanagisawa, Kensuke Kaneko, Hiroaki Ikeda, Sumika Iwata, Atsuya Muranaka, Hiroyuki Koshino, Noeka Nagao, Susumu Watari, Shinichi Nishimura, Naoya Shinzato, Hiroyasu Onaka, Hideaki Kakeya","doi":"10.1038/s41429-025-00821-y","DOIUrl":"10.1038/s41429-025-00821-y","url":null,"abstract":"The combined-culture of actinomycetes with mycolic acid-containing bacteria (MACB) Tsukamurella pulmonis TP-B0596 is a promising strategy to produce cryptic metabolites in actinomycetes. In this study, Streptomyces sp. 23-50 was identified as an appropriate strain for co-culturing with T. pulmonis TP-B0596 using on-gel combined-culture screening of 160 strains of actinomycetes. A new pyranonaphthoquinone, actinoquinonal A (1), along with two known congeners, compound 2 and mevashuntin (3), were isolated from the combined-culture of Streptomyces sp. 23-50 with T. pulmonis TP-B0596 based on global natural product social (GNPS) molecular networking. The planar structures of 1–3 were elucidated by analyzing 2D nuclear magnetic resonance (NMR) and LC-MS/MS spectral data, and the absolute configurations of 1 and 3 were unambiguously determined by comparing experimental and calculated ECD spectra. Moreover, the combined-culture characteristic metabolites, including 3, were enhanced when Streptomyces sp. 23-50 was cultured in the presence of pravastatin, an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase in the mevalonate pathway, suggesting that T. pulmonis TP-B0596 triggered a shunt in the mevalonate pathway of Streptomyces sp. 23-50. Notably, compounds 1 and 3 exhibited cytotoxicity against human cervical epithelioid carcinoma HeLa S3 (IC50 = 60.5 μM for 1, 0.67 μM for 3) and human colorectal cancer HT29 cells (IC50 = 101.9 μM for 1, 0.45 μM for 3).","PeriodicalId":54884,"journal":{"name":"Journal of Antibiotics","volume":"78 6","pages":"350-358"},"PeriodicalIF":2.7,"publicationDate":"2025-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144058757","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-04-15DOI: 10.1038/s41429-025-00820-z
Toshiaki Sunazuka
{"title":"In memory of Professor Amos B. Smith III (26 August 1944 - 3 February 2025)","authors":"Toshiaki Sunazuka","doi":"10.1038/s41429-025-00820-z","DOIUrl":"10.1038/s41429-025-00820-z","url":null,"abstract":"","PeriodicalId":54884,"journal":{"name":"Journal of Antibiotics","volume":"78 6","pages":"392-393"},"PeriodicalIF":2.7,"publicationDate":"2025-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41429-025-00820-z.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145123263","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-04-07DOI: 10.1038/s41429-025-00819-6
Takayoshi Awakawa
As research into the biosynthesis of natural products has matured, the biosynthetic pathways of common skeletons have been identified one after another, and attention is now being focused on research into the biosynthetic machineries of compounds with rare skeletons. Such research has the potential for leading to the discovery of new biosynthetic enzymes and artificial biosynthesis of unnatural compounds. In this study, I introduce the biosynthetic research on altemicidin, SB-203207, and SB-203208, which are rare natural products containing sulfonamide and azaindane skeletons. Further, self-resistance gene mining, the biosynthetic machineries of aminoacyl transferases, the synthesis of sulfonamides and azaindanes, and the structural basis and reaction mechanism of the biosynthetic enzyme SzbP, which uses beta-nicotinamide adenine dinucleotide (β-NAD) and S-adenosylmethionine (SAM) as substrates to create the first intermediate in the biosynthesis, are discussed in detail.
{"title":"Biosynthesis of antibiotics with sulfonamide and azaindane moieties","authors":"Takayoshi Awakawa","doi":"10.1038/s41429-025-00819-6","DOIUrl":"10.1038/s41429-025-00819-6","url":null,"abstract":"As research into the biosynthesis of natural products has matured, the biosynthetic pathways of common skeletons have been identified one after another, and attention is now being focused on research into the biosynthetic machineries of compounds with rare skeletons. Such research has the potential for leading to the discovery of new biosynthetic enzymes and artificial biosynthesis of unnatural compounds. In this study, I introduce the biosynthetic research on altemicidin, SB-203207, and SB-203208, which are rare natural products containing sulfonamide and azaindane skeletons. Further, self-resistance gene mining, the biosynthetic machineries of aminoacyl transferases, the synthesis of sulfonamides and azaindanes, and the structural basis and reaction mechanism of the biosynthetic enzyme SzbP, which uses beta-nicotinamide adenine dinucleotide (β-NAD) and S-adenosylmethionine (SAM) as substrates to create the first intermediate in the biosynthesis, are discussed in detail.","PeriodicalId":54884,"journal":{"name":"Journal of Antibiotics","volume":"78 6","pages":"341-349"},"PeriodicalIF":2.7,"publicationDate":"2025-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143804890","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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