Pub Date : 2025-06-12DOI: 10.1038/s41429-025-00840-9
Asahi Hirata, Miho Sumiyoshi, Hazuki Fujita, Momoko Akimoto, Mary Hannah Rose A. Padayao, Yuto Eguchi, Maki Matsuura, Miyuki Otsuka, Kuninobu Inada, Aiko Teshima, Kenji Arakawa
Streptomyces rochei 7434AN4 produces two structurally unrelated polyketide antibiotics, lankacidin (LC) and lankamycin (LM), and their biosynthesis is tightly controlled by 2,3-disubstituted butenolide-type signaling molecules SRB1 and SRB2. We here investigated the distribution of 2,3-disubstituted butenolides (SRB-type butenolides) among randomly selected 122 Streptomyces strains using two approaches; (1) feeding of their culture extracts into an srrX-deficient strain KA20 of S. rochei, and (2) co-fermentation with strain KA20. All the randomly selected donor strains, except for Streptomyces cellostaticus (a LC and LM producer), failed to restore LC and LM production in strain KA20. These findings strongly revealed the rare distribution of SRB-type butenolide molecules in Streptomyces species. One of the SRB-type butenolide, SAB1, an inducing molecule for nikkomycin production in Streptomyces ansochromogenes, was unable to restore antibiotic production in strain KA20 even at 1 mM concentration. Furthermore, we noticed the accumulation of 4-dehydroxy-SRB1 as a novel compound when SRB1 was fed into strain KA20. Purified 4-dehydroxy-SRB1 has no inducing activity of antibiotic production in strain KA20 even at 1000-fold higher concentration (50 µM) against a minimum inducing concentration of natural SRB1 (40 nM). These findings suggested the importance of the length of a hydrocarbon chain attached at C-2 and a hydroxyl group at C-4 for inducing activity in S. rochei.
{"title":"Rare distribution of butenolide-type signaling molecules among Streptomyces strains and functional importance as inducing factors for secondary metabolite production in Streptomyces rochei 7434AN4","authors":"Asahi Hirata, Miho Sumiyoshi, Hazuki Fujita, Momoko Akimoto, Mary Hannah Rose A. Padayao, Yuto Eguchi, Maki Matsuura, Miyuki Otsuka, Kuninobu Inada, Aiko Teshima, Kenji Arakawa","doi":"10.1038/s41429-025-00840-9","DOIUrl":"10.1038/s41429-025-00840-9","url":null,"abstract":"Streptomyces rochei 7434AN4 produces two structurally unrelated polyketide antibiotics, lankacidin (LC) and lankamycin (LM), and their biosynthesis is tightly controlled by 2,3-disubstituted butenolide-type signaling molecules SRB1 and SRB2. We here investigated the distribution of 2,3-disubstituted butenolides (SRB-type butenolides) among randomly selected 122 Streptomyces strains using two approaches; (1) feeding of their culture extracts into an srrX-deficient strain KA20 of S. rochei, and (2) co-fermentation with strain KA20. All the randomly selected donor strains, except for Streptomyces cellostaticus (a LC and LM producer), failed to restore LC and LM production in strain KA20. These findings strongly revealed the rare distribution of SRB-type butenolide molecules in Streptomyces species. One of the SRB-type butenolide, SAB1, an inducing molecule for nikkomycin production in Streptomyces ansochromogenes, was unable to restore antibiotic production in strain KA20 even at 1 mM concentration. Furthermore, we noticed the accumulation of 4-dehydroxy-SRB1 as a novel compound when SRB1 was fed into strain KA20. Purified 4-dehydroxy-SRB1 has no inducing activity of antibiotic production in strain KA20 even at 1000-fold higher concentration (50 µM) against a minimum inducing concentration of natural SRB1 (40 nM). These findings suggested the importance of the length of a hydrocarbon chain attached at C-2 and a hydroxyl group at C-4 for inducing activity in S. rochei.","PeriodicalId":54884,"journal":{"name":"Journal of Antibiotics","volume":"78 8","pages":"488-499"},"PeriodicalIF":2.7,"publicationDate":"2025-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12301235/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144287140","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}
The screening of antibiotics derived from microbial resources to combat vancomycin-resistant enterococci (VRE) revealed that a culture of marine-derived Peribacillus sp. KDM594 exhibited significant therapeutic efficacy in an infected in vivo-mimic silkworm model. Bioassay-guided purification led to the isolation of micrococcins P1 (1) and P2 (2), which exhibited potent antimicrobial activities against Gram-positive bacteria, including VRE, methicillin-resistant Staphylococcus aureus (MRSA), and Mycobacterium spp., with MIC values ranging from 0.25 to 8.0 µg ml−1 using the microdilution method. In the silkworm models infected with VRE or MRSA, 1 and 2 exerted moderate therapeutic effects, with ED50 values ranging from 3.2 to 51 µg larva−1 g−1. Furthermore, a pharmacokinetic analysis revealed that 2 was metabolized to 1 in the silkworm hemolymph, and their elimination half-lives were 3.2 and 3.0 h, respectively. These results suggest that micrococcins are promising lead compounds for the development of anti-VRE and MRSA drugs.
{"title":"Micrococcins from Peribacillus sp. KDM594; efficacy against vancomycin-resistant enterococci and drug metabolism in a silkworm model","authors":"Akiho Yagi, Mayu Sato, Katsuki Kikuchi, Akito Taniguchi, Takashi Fukuda, Ryuji Uchida","doi":"10.1038/s41429-025-00838-3","DOIUrl":"10.1038/s41429-025-00838-3","url":null,"abstract":"The screening of antibiotics derived from microbial resources to combat vancomycin-resistant enterococci (VRE) revealed that a culture of marine-derived Peribacillus sp. KDM594 exhibited significant therapeutic efficacy in an infected in vivo-mimic silkworm model. Bioassay-guided purification led to the isolation of micrococcins P1 (1) and P2 (2), which exhibited potent antimicrobial activities against Gram-positive bacteria, including VRE, methicillin-resistant Staphylococcus aureus (MRSA), and Mycobacterium spp., with MIC values ranging from 0.25 to 8.0 µg ml−1 using the microdilution method. In the silkworm models infected with VRE or MRSA, 1 and 2 exerted moderate therapeutic effects, with ED50 values ranging from 3.2 to 51 µg larva−1 g−1. Furthermore, a pharmacokinetic analysis revealed that 2 was metabolized to 1 in the silkworm hemolymph, and their elimination half-lives were 3.2 and 3.0 h, respectively. These results suggest that micrococcins are promising lead compounds for the development of anti-VRE and MRSA drugs.","PeriodicalId":54884,"journal":{"name":"Journal of Antibiotics","volume":"78 8","pages":"481-487"},"PeriodicalIF":2.7,"publicationDate":"2025-06-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144276748","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 : 2025-06-09DOI: 10.1038/s41429-025-00827-6
Ólafur S. Andrésson, Douglas E. Berg, Patrice Courvalin, Michel De Wilde, Morimasa Yagisawa, Thomas J. White, Vicky Davies, Robin Davies, Jeremy Davies
{"title":"Obituary of Professor Julian E. Davies","authors":"Ólafur S. Andrésson, Douglas E. Berg, Patrice Courvalin, Michel De Wilde, Morimasa Yagisawa, Thomas J. White, Vicky Davies, Robin Davies, Jeremy Davies","doi":"10.1038/s41429-025-00827-6","DOIUrl":"10.1038/s41429-025-00827-6","url":null,"abstract":"","PeriodicalId":54884,"journal":{"name":"Journal of Antibiotics","volume":"78 7","pages":"449-456"},"PeriodicalIF":2.7,"publicationDate":"2025-06-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41429-025-00827-6.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144250958","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 : 2025-06-09DOI: 10.1038/s41429-025-00836-5
Yu Tu, Jinxin Zhang, Lei Cai, Ling Liu
Two new butanolides asperbutanolides A (1) and B (2), and a new fatty acid derivative omphalotol C (3), along with 5 known compounds were isolated from the ethyl acetate (EtOAc) crude extract of the deep-sea-derived fungus Aspergillus tabacinus LW82 guided by OSMAC (One Strain Many Compounds) strategy. The structural elucidation and absolute configuration determination of these compounds were achieved by comprehensive spectroscopic analysis, including nuclear magnetic resonance (NMR), high-resolution electrospray ionization mass spectrometry (HRESIMS), and [Rh2(OCOCF3)4]-induced electronic circular dichroism (ECD) experiment. Compound 1 exhibited antibacterial activity against Pseudomonas syringae pv. Lachrymans with MIC value of 64 μg ml−1. Furthermore, compound 6 displayed significant antifungal efficacy against Cryptococcus gattii R265 and 3284G14, with both MIC values of 8 μg ml−1, comparable to the antifungal agent fluconazole.
{"title":"New antimicrobial butanolides from a deep sea-derived fungus Aspergillus tabacinus LW82","authors":"Yu Tu, Jinxin Zhang, Lei Cai, Ling Liu","doi":"10.1038/s41429-025-00836-5","DOIUrl":"10.1038/s41429-025-00836-5","url":null,"abstract":"Two new butanolides asperbutanolides A (1) and B (2), and a new fatty acid derivative omphalotol C (3), along with 5 known compounds were isolated from the ethyl acetate (EtOAc) crude extract of the deep-sea-derived fungus Aspergillus tabacinus LW82 guided by OSMAC (One Strain Many Compounds) strategy. The structural elucidation and absolute configuration determination of these compounds were achieved by comprehensive spectroscopic analysis, including nuclear magnetic resonance (NMR), high-resolution electrospray ionization mass spectrometry (HRESIMS), and [Rh2(OCOCF3)4]-induced electronic circular dichroism (ECD) experiment. Compound 1 exhibited antibacterial activity against Pseudomonas syringae pv. Lachrymans with MIC value of 64 μg ml−1. Furthermore, compound 6 displayed significant antifungal efficacy against Cryptococcus gattii R265 and 3284G14, with both MIC values of 8 μg ml−1, comparable to the antifungal agent fluconazole.","PeriodicalId":54884,"journal":{"name":"Journal of Antibiotics","volume":"78 8","pages":"472-480"},"PeriodicalIF":2.7,"publicationDate":"2025-06-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144259388","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 : 2025-06-06DOI: 10.1038/s41429-025-00834-7
Mahwish Saleem, Mona Siddiqui, Hafiza Noor ul Huda, Shaista Urooj, Bushra Jabeen, Fouzia Zeeshan Khan, Yasir Raza, Nisar Ahmed Shar, Saeed Khan, Ayaz Ahemd, Zulfiqar Ali Mirani
This study investigated imipenem-resistant Pseudomonas aeruginosa (P. aeruginosa) isolates recovered from various ready-to-eat food items. Isolates were identified as P. aeruginosa based on growth on selective P-Pseudomonas media and confirmed by PCR amplification of the oprI and oprL genes. These isolates formed biofilms under laboratory conditions at 35 °C in Tryptic Soy Broth (TSB). The biofilms were induced by a sub-inhibitory dose of imipenem. Two types of biofilm aggregates were observed: surface-bound biofilms and unbound cell aggregates. Surface-bound biofilms appeared after 48 h of incubation and reached maximum biomass after 96 h. Unbound aggregates were observed after 72 h of incubation. The biomass of aggregates was measured using a crystal violet binding assay. Further characterization revealed two types of unbound or floating aggregates: aggregates detached from surface-bound biofilms and spontaneously formed cell clusters. Both aggregate types exhibited similar imipenem resistance profiles. Comparative analysis of surface-bound and unbound biofilm cells revealed that surface-bound cells were more hydrophobic and relatively more resistant to high temperatures. Both types of aggregates survived at 80 °C for 12 h. Atomic force microscopy showed that surface-bound P. aeruginosa cells were stiffer, with an average force constant of 56.36 ± 5.21 pN nm−1, compared to cells from unbound aggregates [44.55 ± 4.87 pN nm−1]. Similarly, surface-bound cells exhibited greater adhesiveness, with an average adhesion force of 553.25 ± 62.18 pN, whereas cells from floating aggregates demonstrated lower adhesion force values, averaging 451.81 ± 58.32 pN.
{"title":"Survival strategies of imipenem-resistant P. aeruginosa: a comparative analysis of surface-bound biofilms and unbound aggregates","authors":"Mahwish Saleem, Mona Siddiqui, Hafiza Noor ul Huda, Shaista Urooj, Bushra Jabeen, Fouzia Zeeshan Khan, Yasir Raza, Nisar Ahmed Shar, Saeed Khan, Ayaz Ahemd, Zulfiqar Ali Mirani","doi":"10.1038/s41429-025-00834-7","DOIUrl":"10.1038/s41429-025-00834-7","url":null,"abstract":"This study investigated imipenem-resistant Pseudomonas aeruginosa (P. aeruginosa) isolates recovered from various ready-to-eat food items. Isolates were identified as P. aeruginosa based on growth on selective P-Pseudomonas media and confirmed by PCR amplification of the oprI and oprL genes. These isolates formed biofilms under laboratory conditions at 35 °C in Tryptic Soy Broth (TSB). The biofilms were induced by a sub-inhibitory dose of imipenem. Two types of biofilm aggregates were observed: surface-bound biofilms and unbound cell aggregates. Surface-bound biofilms appeared after 48 h of incubation and reached maximum biomass after 96 h. Unbound aggregates were observed after 72 h of incubation. The biomass of aggregates was measured using a crystal violet binding assay. Further characterization revealed two types of unbound or floating aggregates: aggregates detached from surface-bound biofilms and spontaneously formed cell clusters. Both aggregate types exhibited similar imipenem resistance profiles. Comparative analysis of surface-bound and unbound biofilm cells revealed that surface-bound cells were more hydrophobic and relatively more resistant to high temperatures. Both types of aggregates survived at 80 °C for 12 h. Atomic force microscopy showed that surface-bound P. aeruginosa cells were stiffer, with an average force constant of 56.36 ± 5.21 pN nm−1, compared to cells from unbound aggregates [44.55 ± 4.87 pN nm−1]. Similarly, surface-bound cells exhibited greater adhesiveness, with an average adhesion force of 553.25 ± 62.18 pN, whereas cells from floating aggregates demonstrated lower adhesion force values, averaging 451.81 ± 58.32 pN.","PeriodicalId":54884,"journal":{"name":"Journal of Antibiotics","volume":"78 8","pages":"500-510"},"PeriodicalIF":2.7,"publicationDate":"2025-06-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144250959","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 : 2025-06-03DOI: 10.1038/s41429-025-00833-8
Saloni V. Koli, Snehal V. Mali, Jisha Geevarghese
The global health problem of carbapenem-resistant and hypervirulent Klebsiella pneumoniae (CRKP) is exacerbated by the lack of effective treatments and increasing resistance. This study compares the clinical impact, resistance mechanisms, and prevalence of CR-hvKP in industrialized and emerging nations, analyzing 300 papers from national databases and selecting 70 for further examination. Treatment effectiveness, clinical outcomes, resistance mechanisms, and prevalence were assessed in the study, which concentrated on CRKP and hvKP strains that carried virulence genes (rmpA, aerobactin, yersiniabactin) and carbapenemase genes (blaKPC, blaNDM, blaOXA-12). With 25% of studies identifying blaOXA-48, 30% reporting blaKPC, and 45% tying blaNDM to resistance, analysis showed β-lactamase genes are mostly responsible for carbapenem resistance in Klebsiella pneumoniae strains. Resistance rates for CR-hvKP range from 4.4% to 100% in India, where the condition is disproportionately common. Clinical results are alarming: hospital-admitted patients had death rates ranging from 30% to 60% and morbidity rates as high as 90%. The study emphasizes how plasmid-mediated resistance, immune evasion mechanisms, and enhanced biofilm development contribute to the pathophysiology of CR-hvKP, making therapy more difficult. Urgent action is needed to battle CR-hvKP and lessen its catastrophic clinical impact, as it is more common in India than developed countries.
{"title":"“Global divide in carbapenem resistance and hypervirulence of Klebsiella pneumonia: comparing trends in India and developed nations”- a comprehensive review","authors":"Saloni V. Koli, Snehal V. Mali, Jisha Geevarghese","doi":"10.1038/s41429-025-00833-8","DOIUrl":"10.1038/s41429-025-00833-8","url":null,"abstract":"The global health problem of carbapenem-resistant and hypervirulent Klebsiella pneumoniae (CRKP) is exacerbated by the lack of effective treatments and increasing resistance. This study compares the clinical impact, resistance mechanisms, and prevalence of CR-hvKP in industrialized and emerging nations, analyzing 300 papers from national databases and selecting 70 for further examination. Treatment effectiveness, clinical outcomes, resistance mechanisms, and prevalence were assessed in the study, which concentrated on CRKP and hvKP strains that carried virulence genes (rmpA, aerobactin, yersiniabactin) and carbapenemase genes (blaKPC, blaNDM, blaOXA-12). With 25% of studies identifying blaOXA-48, 30% reporting blaKPC, and 45% tying blaNDM to resistance, analysis showed β-lactamase genes are mostly responsible for carbapenem resistance in Klebsiella pneumoniae strains. Resistance rates for CR-hvKP range from 4.4% to 100% in India, where the condition is disproportionately common. Clinical results are alarming: hospital-admitted patients had death rates ranging from 30% to 60% and morbidity rates as high as 90%. The study emphasizes how plasmid-mediated resistance, immune evasion mechanisms, and enhanced biofilm development contribute to the pathophysiology of CR-hvKP, making therapy more difficult. Urgent action is needed to battle CR-hvKP and lessen its catastrophic clinical impact, as it is more common in India than developed countries.","PeriodicalId":54884,"journal":{"name":"Journal of Antibiotics","volume":"78 8","pages":"457-471"},"PeriodicalIF":2.7,"publicationDate":"2025-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144217624","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}
Polymyxin B (PMB) is a polypeptide antibiotic active against multidrug-resistant bacteria, including multidrug-resistant Pseudomonas aeruginosa (MDRP). However, PMB frequently initiates serious acute renal failure (ARF). Our recent study demonstrated that PMB-induced ARF is triggered by inflammatory responses mediated by activation of the NOD-like receptors protein 3 (NLRP3) inflammasome. Here, we provide evidence that sulfasalazine (SSZ), a clinically-used disease-modifying antirheumatic drug (DMARD), can ameliorate PMB-induced ARF in a mouse model of ARF. Since SSZ strongly inhibited the NLRP3 inflammasome activation induced by PMB in macrophages, as previously demonstrated, the amelioration of PMB-induced ARF appears to be brought about by the inhibition of the NLRP3 inflammasome activation. Thus, if SSZ could be effectively utilized in clinical practice, it may be possible to overcome ARF caused by polypeptide antibiotics.
{"title":"The antirheumatic drug sulfasalazine ameliorates acute renal failure (ARF) induced by polymyxin B","authors":"Kohei Otani, Tomohiro Kagi, Takuya Noguchi, Sara Suzuki, Yusuke Hirata, Atsushi Matsuzawa","doi":"10.1038/s41429-025-00835-6","DOIUrl":"10.1038/s41429-025-00835-6","url":null,"abstract":"Polymyxin B (PMB) is a polypeptide antibiotic active against multidrug-resistant bacteria, including multidrug-resistant Pseudomonas aeruginosa (MDRP). However, PMB frequently initiates serious acute renal failure (ARF). Our recent study demonstrated that PMB-induced ARF is triggered by inflammatory responses mediated by activation of the NOD-like receptors protein 3 (NLRP3) inflammasome. Here, we provide evidence that sulfasalazine (SSZ), a clinically-used disease-modifying antirheumatic drug (DMARD), can ameliorate PMB-induced ARF in a mouse model of ARF. Since SSZ strongly inhibited the NLRP3 inflammasome activation induced by PMB in macrophages, as previously demonstrated, the amelioration of PMB-induced ARF appears to be brought about by the inhibition of the NLRP3 inflammasome activation. Thus, if SSZ could be effectively utilized in clinical practice, it may be possible to overcome ARF caused by polypeptide antibiotics.","PeriodicalId":54884,"journal":{"name":"Journal of Antibiotics","volume":"78 8","pages":"511-515"},"PeriodicalIF":2.7,"publicationDate":"2025-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144210292","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}
Cancer stem cells (CSCs) play a crucial role in cancer progression, recurrence, and therapy resistance through their abilities to self-renew, differentiate, and evade treatment. Disrupting the interaction between CSCs and their tumor microenvironment, especially cancer-associated fibroblasts (CAFs), represents a promising therapeutic strategy. We screened microbial metabolites to identify compounds that specifically inhibit anchorage-independent (3D) growth, a key characteristic of CSCs, in the presence of CAF-conditioned medium (CAF-CM). Two new oligomycin analogs, oligomycins EX-1 (1) and 2 (2), were successfully isolated from Nocardia sp. MK165-SF8. Structural analysis using NMR and MS techniques revealed their distinctive chemical characteristics, particularly the presence of an exomethylene group. In biological assays, 1 and 2 demonstrated potent inhibitory activity against mitochondrial complex V, comparable to oligomycin A. Additionally, they showed enhanced effectiveness in suppressing both 3D growth and the expression of CD44 variants in pancreatic cancer cells cultured in CAF-CM.
{"title":"New oligomycin derivatives inhibit anchorage-independent growth of pancreatic cancer cells","authors":"Daisuke Tatsuda, Masahide Amemiya, Chisato Nosaka, Yumiko Kubota, Ryuichi Sawa, Hideyuki Muramatsu, Masayuki Igarashi, Junjiro Yoshida, Tomokazu Ohishi, Manabu Kawada","doi":"10.1038/s41429-025-00832-9","DOIUrl":"10.1038/s41429-025-00832-9","url":null,"abstract":"Cancer stem cells (CSCs) play a crucial role in cancer progression, recurrence, and therapy resistance through their abilities to self-renew, differentiate, and evade treatment. Disrupting the interaction between CSCs and their tumor microenvironment, especially cancer-associated fibroblasts (CAFs), represents a promising therapeutic strategy. We screened microbial metabolites to identify compounds that specifically inhibit anchorage-independent (3D) growth, a key characteristic of CSCs, in the presence of CAF-conditioned medium (CAF-CM). Two new oligomycin analogs, oligomycins EX-1 (1) and 2 (2), were successfully isolated from Nocardia sp. MK165-SF8. Structural analysis using NMR and MS techniques revealed their distinctive chemical characteristics, particularly the presence of an exomethylene group. In biological assays, 1 and 2 demonstrated potent inhibitory activity against mitochondrial complex V, comparable to oligomycin A. Additionally, they showed enhanced effectiveness in suppressing both 3D growth and the expression of CD44 variants in pancreatic cancer cells cultured in CAF-CM.","PeriodicalId":54884,"journal":{"name":"Journal of Antibiotics","volume":"78 7","pages":"436-441"},"PeriodicalIF":2.7,"publicationDate":"2025-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144210291","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 : 2025-05-29DOI: 10.1038/s41429-025-00831-w
Rana Eshimy, Ahmed I. El-Batal, Farag M. Mosallam
Traditional antifungal drugs are ineffective against multidrug-resistant Candida infections. The goal of this work is the preparation of Clotrimazole Selenium Nano-composite (CZ-Se-NC) suspension and CZ-Se-NC-gel for combating clotrimazole-resistant Candida albicans (NCRRT-CZR) infection. CZ-Se-NC is prepared by simple homogenization ultra-sonication technique and validated by SEM-EDX mapping, DLS, Zeta potential and FT-IR that confirm formulation of Nano-composite. In vitro results demonstrated that CZ-Se-NC and formulated CZ-Se-NC gel have the same anti-candidal activity showing inhibitory zone values 31.0 ± 0.931 mm, 27.0 ± 1.004 and MIC values 0.625, 1.25 µg ml−1 and MFC values 2.5, 5 µg ml−1 against C. albicans (ATCC 10231) and C. albicans (NCRRT-CZR), respectively. Non-treated C. albicans (NCRRT-CZR) show biofilm formation 100% that become 8.62% after treatment with CZ-Se-NC at 1/2MIC. Virulence genes ALS1, Plb1, CDR1 and ERG11 expression of C. albicans (NCRRT-CZR) were down regulated by 76.67, 87.06, 53.67 and 76.01%, respectively, after treatment with CZ-Se-NC. The CZ-Se-NC gel formula gradually releases clotrimazole and selenium 41 and 48% after 24 h, respectively. Furthermore, after deep dermal infections by C. albicans (NCRRT-CZR), treated mice exhibit excellent skin infection healing performance as evidenced by the significantly reduced inflammation and complete skin infection clearance after treatment with CZ-Se-NC gel. Gamma rays show a negative impact on the CZ-Se-NC size distribution. The formulation of CZ-Se-NC as a topical gel formulation could provide an opportunity to develop a cost-effective approach to achieve optimal therapeutic performance against resistant fungal infections at a much lower dose than is currently used. Additionally, it will enhance patient compliance by reducing the frequent application.
{"title":"A novel clotrimazole selenium nano-composite for combating deep dermal Candida albicans infections and virulence genes","authors":"Rana Eshimy, Ahmed I. El-Batal, Farag M. Mosallam","doi":"10.1038/s41429-025-00831-w","DOIUrl":"10.1038/s41429-025-00831-w","url":null,"abstract":"Traditional antifungal drugs are ineffective against multidrug-resistant Candida infections. The goal of this work is the preparation of Clotrimazole Selenium Nano-composite (CZ-Se-NC) suspension and CZ-Se-NC-gel for combating clotrimazole-resistant Candida albicans (NCRRT-CZR) infection. CZ-Se-NC is prepared by simple homogenization ultra-sonication technique and validated by SEM-EDX mapping, DLS, Zeta potential and FT-IR that confirm formulation of Nano-composite. In vitro results demonstrated that CZ-Se-NC and formulated CZ-Se-NC gel have the same anti-candidal activity showing inhibitory zone values 31.0 ± 0.931 mm, 27.0 ± 1.004 and MIC values 0.625, 1.25 µg ml−1 and MFC values 2.5, 5 µg ml−1 against C. albicans (ATCC 10231) and C. albicans (NCRRT-CZR), respectively. Non-treated C. albicans (NCRRT-CZR) show biofilm formation 100% that become 8.62% after treatment with CZ-Se-NC at 1/2MIC. Virulence genes ALS1, Plb1, CDR1 and ERG11 expression of C. albicans (NCRRT-CZR) were down regulated by 76.67, 87.06, 53.67 and 76.01%, respectively, after treatment with CZ-Se-NC. The CZ-Se-NC gel formula gradually releases clotrimazole and selenium 41 and 48% after 24 h, respectively. Furthermore, after deep dermal infections by C. albicans (NCRRT-CZR), treated mice exhibit excellent skin infection healing performance as evidenced by the significantly reduced inflammation and complete skin infection clearance after treatment with CZ-Se-NC gel. Gamma rays show a negative impact on the CZ-Se-NC size distribution. The formulation of CZ-Se-NC as a topical gel formulation could provide an opportunity to develop a cost-effective approach to achieve optimal therapeutic performance against resistant fungal infections at a much lower dose than is currently used. Additionally, it will enhance patient compliance by reducing the frequent application.","PeriodicalId":54884,"journal":{"name":"Journal of Antibiotics","volume":"78 7","pages":"418-435"},"PeriodicalIF":2.7,"publicationDate":"2025-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144183225","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 : 2025-05-19DOI: 10.1038/s41429-025-00830-x
Shuaiqi Ma, Shixin Li, Li Song, Asma Riaz, Ruifeng Huang, Shaofen Zhou, Jingnan Qiu, Zonglin Chu, Jian He
A new cyclic tetrapeptide named Cereusitin B (1), along with a number of known cyclic dipeptides was isolated from the fermentation broth of a marine-associated Bacillus sp. I-2. The structure of Cereusitin B, cyclo-(l-phenylalanyl-trans-4-hydroxy-l-prolyl-l-leucyl-l-alanine), was determined through extensive analysis using high-resolution electrospray ionization mass spectrometry and NMR spectral data (1D, 2D NMR), and its identity was further confirmed by Marfey’ method and chemical synthesis. The antimicrobial activity tests showed that compound 2 was moderately active against Candida albicans with a MIC value of 125 µg mL−1, while the other compounds exhibited no antimicrobial activity at the experimental concentrations. In addition, compound 1 showed the ability to inhibit the formation of S. aureus biofilm.
{"title":"Isolation and synthesis of a new cyclic tetrapeptide from marine-associated Bacillus sp. and its bacterial biofilm formation inhibitory activity","authors":"Shuaiqi Ma, Shixin Li, Li Song, Asma Riaz, Ruifeng Huang, Shaofen Zhou, Jingnan Qiu, Zonglin Chu, Jian He","doi":"10.1038/s41429-025-00830-x","DOIUrl":"10.1038/s41429-025-00830-x","url":null,"abstract":"A new cyclic tetrapeptide named Cereusitin B (1), along with a number of known cyclic dipeptides was isolated from the fermentation broth of a marine-associated Bacillus sp. I-2. The structure of Cereusitin B, cyclo-(l-phenylalanyl-trans-4-hydroxy-l-prolyl-l-leucyl-l-alanine), was determined through extensive analysis using high-resolution electrospray ionization mass spectrometry and NMR spectral data (1D, 2D NMR), and its identity was further confirmed by Marfey’ method and chemical synthesis. The antimicrobial activity tests showed that compound 2 was moderately active against Candida albicans with a MIC value of 125 µg mL−1, while the other compounds exhibited no antimicrobial activity at the experimental concentrations. In addition, compound 1 showed the ability to inhibit the formation of S. aureus biofilm.","PeriodicalId":54884,"journal":{"name":"Journal of Antibiotics","volume":"78 7","pages":"408-417"},"PeriodicalIF":2.7,"publicationDate":"2025-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144103260","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}
京公网安备 11010802042870号
京ICP备2023020795号-1
扫码关注我们
求助内容：
应助结果提醒方式：