Pub Date : 2025-11-20DOI: 10.1038/s41429-025-00881-0
Jiayi Yu, Richiro Ushimaru
Natural products provide privileged scaffolds for drug discovery, yet their stereochemical complexity often exceeds the limits of synthetic chemistry. Genome mining has emerged as a transformative strategy to uncover cryptic biosynthetic gene clusters and enzymes with noncanonical activities. Recent studies have revealed enzymes exhibiting unusual stereoselectivities, thereby expanding the enzymatic repertoire for constructing complex chiral architectures. Comparative analyses indicated that subtle variations in sequence and active-site environments produce diverse stereochemical outcomes across enzyme families. This review highlights representative examples of stereodivergent enzymes identified through genome- or sequence-guided approaches, emphasizing their substrate scope, catalytic mechanisms, and stereocontrol features. These advances not only deepen our mechanistic understanding of stereoselectivity but also lay the groundwork for rational enzyme engineering and the development of next-generation biocatalysts in pharmaceutical synthesis.
{"title":"Genome mining-driven discovery of enzymes catalyzing stereodivergent transformations.","authors":"Jiayi Yu, Richiro Ushimaru","doi":"10.1038/s41429-025-00881-0","DOIUrl":"https://doi.org/10.1038/s41429-025-00881-0","url":null,"abstract":"<p><p>Natural products provide privileged scaffolds for drug discovery, yet their stereochemical complexity often exceeds the limits of synthetic chemistry. Genome mining has emerged as a transformative strategy to uncover cryptic biosynthetic gene clusters and enzymes with noncanonical activities. Recent studies have revealed enzymes exhibiting unusual stereoselectivities, thereby expanding the enzymatic repertoire for constructing complex chiral architectures. Comparative analyses indicated that subtle variations in sequence and active-site environments produce diverse stereochemical outcomes across enzyme families. This review highlights representative examples of stereodivergent enzymes identified through genome- or sequence-guided approaches, emphasizing their substrate scope, catalytic mechanisms, and stereocontrol features. These advances not only deepen our mechanistic understanding of stereoselectivity but also lay the groundwork for rational enzyme engineering and the development of next-generation biocatalysts in pharmaceutical synthesis.</p>","PeriodicalId":54884,"journal":{"name":"Journal of Antibiotics","volume":" ","pages":""},"PeriodicalIF":2.7,"publicationDate":"2025-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145558217","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 : 2025-11-20DOI: 10.1038/s41429-025-00875-y
Shimaa El Baz, Abdelfattah H. Eladl, Reham A. El-Shafei, Mohamed A. Elmorsy
The objective of this study was to investigate the prevalence and phenotypic identification of antimicrobial resistance of K. pneumoniae and K. oxytoca recovered from backyard broiler chickens and their human contacts. The serotypes and genotypes of antibiotic resistance genes of K. pneumoniae isolates were investigated. A total of 80 samples were collected from backyard broiler chickens that showed signs of illness, sneezing, coughing, and diarrhea. Twenty stool samples were collected from individuals who had been in contact simultaneously. In total, 19 Klebsiella species were isolated, 12 of which were from broiler chicken samples and seven from human stool samples. Recovery rates of K. pneumoniae were 11.3% (n = 9/80) and 15% (n = 3/20) of broiler and human stool samples, respectively. K. oxytoca was detected in 3 of 80 (3.75%) broiler chicken and 4 of 20 (20%) human stool samples. Antimicrobial susceptibility showed that all 19 Klebsiella isolates were resistant to erythromycin and clindamycin (100%), followed by penicillin (94.7%) and ampicillin (84.3%). Within the 12 K. pneumoniae isolates, the most common serotype was K1. Antibiotic resistance gene profile of K. pneumoniae isolates was observed, with a high carrying rate of the macrolide gene ermB (91.7%), followed by the β-lactam genes blaTEM (75%) and blaCTX-M1 (66.7%). In conclusion, the emergence of multidrug-resistant (MDR) bacteria, K. pneumoniae and K. oxytoca in broiler backyard chickens and their human contacts is alarming, particularly for erythromycin and clindamycin. This underscores the need for alternatives like vaccination, probiotics, and better biosecurity to combat antimicrobial resistance.
{"title":"Multidrug-resistant Klebsiella pneumoniae and Klebsiella oxytoca isolated from backyard broiler chickens and their contacts with antimicrobial resistance genes of Klebsiella pneumoniae","authors":"Shimaa El Baz, Abdelfattah H. Eladl, Reham A. El-Shafei, Mohamed A. Elmorsy","doi":"10.1038/s41429-025-00875-y","DOIUrl":"10.1038/s41429-025-00875-y","url":null,"abstract":"The objective of this study was to investigate the prevalence and phenotypic identification of antimicrobial resistance of K. pneumoniae and K. oxytoca recovered from backyard broiler chickens and their human contacts. The serotypes and genotypes of antibiotic resistance genes of K. pneumoniae isolates were investigated. A total of 80 samples were collected from backyard broiler chickens that showed signs of illness, sneezing, coughing, and diarrhea. Twenty stool samples were collected from individuals who had been in contact simultaneously. In total, 19 Klebsiella species were isolated, 12 of which were from broiler chicken samples and seven from human stool samples. Recovery rates of K. pneumoniae were 11.3% (n = 9/80) and 15% (n = 3/20) of broiler and human stool samples, respectively. K. oxytoca was detected in 3 of 80 (3.75%) broiler chicken and 4 of 20 (20%) human stool samples. Antimicrobial susceptibility showed that all 19 Klebsiella isolates were resistant to erythromycin and clindamycin (100%), followed by penicillin (94.7%) and ampicillin (84.3%). Within the 12 K. pneumoniae isolates, the most common serotype was K1. Antibiotic resistance gene profile of K. pneumoniae isolates was observed, with a high carrying rate of the macrolide gene ermB (91.7%), followed by the β-lactam genes blaTEM (75%) and blaCTX-M1 (66.7%). In conclusion, the emergence of multidrug-resistant (MDR) bacteria, K. pneumoniae and K. oxytoca in broiler backyard chickens and their human contacts is alarming, particularly for erythromycin and clindamycin. This underscores the need for alternatives like vaccination, probiotics, and better biosecurity to combat antimicrobial resistance.","PeriodicalId":54884,"journal":{"name":"Journal of Antibiotics","volume":"79 1","pages":"50-60"},"PeriodicalIF":2.7,"publicationDate":"2025-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41429-025-00875-y.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145565488","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 : 2025-11-17DOI: 10.1038/s41429-025-00874-z
Yu-Jing Zeng, Yi-Feng Ye, Xu-Ming Mao
Natural products (NPs) from bacteria and fungi have contributed substantially to human health and life. They have particularly attracted attention due to their intriguing bioactivity and complex structures. Biosynthetic gene clusters (BGCs), which encode biosynthetic enzymes to catalyze the biochemical cascade reactions, are responsible for the biosynthesis of NPs. Canonical BGCs have apparent core enzymes to produce several types of NPs according to their disparate skeleton structures. However, recent studies have discovered some BGCs that do not have prominent canonical core enzymes to perform the backbone-defining transformation of NPs, but produce more structurally diverse NPs with intriguing biosynthetic logic. Herein, this type of BGCs is classified as unusual gene clusters (uGCs). In this review, we summarize advances on bacterial and fungal NPs produced from uGCs, the featuring enzymes to produce these NPs, as well as the key distinct biosynthetic steps. Further studies on these uGCs will greatly enrich the genetic and chemical repertoire of microbial NPs.
{"title":"Microbial unusual gene clusters without prominent core enzymes: natural products, biosynthesis and genome mining.","authors":"Yu-Jing Zeng, Yi-Feng Ye, Xu-Ming Mao","doi":"10.1038/s41429-025-00874-z","DOIUrl":"https://doi.org/10.1038/s41429-025-00874-z","url":null,"abstract":"<p><p>Natural products (NPs) from bacteria and fungi have contributed substantially to human health and life. They have particularly attracted attention due to their intriguing bioactivity and complex structures. Biosynthetic gene clusters (BGCs), which encode biosynthetic enzymes to catalyze the biochemical cascade reactions, are responsible for the biosynthesis of NPs. Canonical BGCs have apparent core enzymes to produce several types of NPs according to their disparate skeleton structures. However, recent studies have discovered some BGCs that do not have prominent canonical core enzymes to perform the backbone-defining transformation of NPs, but produce more structurally diverse NPs with intriguing biosynthetic logic. Herein, this type of BGCs is classified as unusual gene clusters (uGCs). In this review, we summarize advances on bacterial and fungal NPs produced from uGCs, the featuring enzymes to produce these NPs, as well as the key distinct biosynthetic steps. Further studies on these uGCs will greatly enrich the genetic and chemical repertoire of microbial NPs.</p>","PeriodicalId":54884,"journal":{"name":"Journal of Antibiotics","volume":" ","pages":""},"PeriodicalIF":2.7,"publicationDate":"2025-11-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145535174","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 : 2025-11-12DOI: 10.1038/s41429-025-00882-z
Md. Mehebub Al Raji, Naoya Oku, Toshihiko Nogawa, Agus Trianto, Yasuhiro Igarashi
{"title":"Correction: Litchficin, a germination inhibitory acyloin from a halophilic Gram-positive bacterium of the genus Litchfieldia","authors":"Md. Mehebub Al Raji, Naoya Oku, Toshihiko Nogawa, Agus Trianto, Yasuhiro Igarashi","doi":"10.1038/s41429-025-00882-z","DOIUrl":"10.1038/s41429-025-00882-z","url":null,"abstract":"","PeriodicalId":54884,"journal":{"name":"Journal of Antibiotics","volume":"79 1","pages":"66-66"},"PeriodicalIF":2.7,"publicationDate":"2025-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41429-025-00882-z.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145508147","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}
Despite decades of investigation, multidrug-resistant bacterial resistance has become the leading health concern globally related to MRSA infections, where conventional antibiotics have failed in this race. However, the development of short cationic antimicrobial peptides with higher efficacy and low cytotoxicity has encouraged our recent exploration. Herein, we describe the synthesis, characterization, and antibacterial evaluation of tetrahydropiperic acid (THPA) conjugate αβ-hybrid peptides, THPA-Lys-tBu-β3,3Ac6c-PEA, P1; THPA-Orn-tBu-β3,3Ac6c-PEA, P2, and THPA-Arg-tBu-β3,3Ac6c-PEA, P3. Our investigation revealed peptide P3 exhibited low hemolytic and best safety index along with higher bactericidal potency against MRSA. Combinatorial study with vancomycin suggested synergistic effect. Mechanistic investigations revealed membrane disruption of MRSA by the peptide. This study suggested that peptide P3 could be an effective therapeutic option to resist the emergence of MRSA-related infections.
{"title":"Antibacterial activity and mechanism of optimized THPA conjugated dipeptides against methicillin-resistant Staphylococcus aureus","authors":"Arti Rathore, Beenish Rashid, Aminur Rahman Sarkar, Shifa Firdous, Rubina Chowdhary, Rakshit Manhas, Faizan Ahmad Magray, Biplab Sarkar, Jyoti Kumari, Rajkishor Rai, Avisek Mahapa","doi":"10.1038/s41429-025-00877-w","DOIUrl":"10.1038/s41429-025-00877-w","url":null,"abstract":"Despite decades of investigation, multidrug-resistant bacterial resistance has become the leading health concern globally related to MRSA infections, where conventional antibiotics have failed in this race. However, the development of short cationic antimicrobial peptides with higher efficacy and low cytotoxicity has encouraged our recent exploration. Herein, we describe the synthesis, characterization, and antibacterial evaluation of tetrahydropiperic acid (THPA) conjugate αβ-hybrid peptides, THPA-Lys-tBu-β3,3Ac6c-PEA, P1; THPA-Orn-tBu-β3,3Ac6c-PEA, P2, and THPA-Arg-tBu-β3,3Ac6c-PEA, P3. Our investigation revealed peptide P3 exhibited low hemolytic and best safety index along with higher bactericidal potency against MRSA. Combinatorial study with vancomycin suggested synergistic effect. Mechanistic investigations revealed membrane disruption of MRSA by the peptide. This study suggested that peptide P3 could be an effective therapeutic option to resist the emergence of MRSA-related infections.","PeriodicalId":54884,"journal":{"name":"Journal of Antibiotics","volume":"79 1","pages":"15-29"},"PeriodicalIF":2.7,"publicationDate":"2025-11-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145490736","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 : 2025-11-07DOI: 10.1038/s41429-025-00871-2
Marwa Elsbaey, Md Towhidul Islam Tarun, Radwan Alnajjar, Takahiro Jomori, Junichi Tanaka, Naoya Oku, Khalid El Sayed, Yasuhiro Igarashi
Breast tumor kinase (Brk) is an intracellular kinase that initiates a downstream oncogenic signaling through phosphorylation of focal adhesion kinase (FAK) and signal transducer and activator of transcription 3 (STAT3). Demethylmycemycin A (DA) was isolated from a sponge-derived Dactylosporangium sp. OK1079. Though known as a microbial dibenzoxazepinone, its biological activity has never been investigated. Previous studies on the marine triterpene sipholenol A identified its perhydrobenzoxepine system as the key pharmacophore that mediated its Brk binding. The bioisosteric similarity of DA to the sipholenol A perhydrobenzoxepine motivated a molecular docking simulation of DA for potential Brk binding. The antiproliferative effect of DA was investigated against diverse prostate cancer (PC) cell lines including LNCaP (castration/hormone-sensitive primary adenocarcinoma), PC3, and 22Rv1 (castration-resistant), in addition to the androgen-independent DU145 cells. LNCaP cells were the most sensitive to the effects of DA, followed by PC3, showing IC50 values of 7.6 and 9.8 μM, respectively. DA treatments significantly reduced the migration and clonogenicity of the LNCaP cells. Western blot analysis indicated the ability of DA to reduce the expression levels of activated Brk, FAK and STAT3 in a dose-dependent manner in both cell lines. DA also decreased the expression levels of the total FAK but didn’t affect the total level of Brk while the expression level of total STAT3 was only suppressed in LNCaP cells. These results highlight the PC proliferation and migration suppressive effects of DA through targeting Brk-FAK-STAT3 axis. DA is a potential prototype hit that can be developed particularly for Brk-expressing PC control.
乳腺肿瘤激酶（Breast tumor kinase, Brk）是一种细胞内激酶，通过局灶黏附激酶（focal adhesion kinase， FAK）和转录信号转导及激活因子3 （signal transducer and activator of transcription, STAT3）的磷酸化启动下游的致癌信号传导。从海绵来源的Dactylosporangium sp. OK1079中分离到去甲基mycemycin A （DA）。虽然被称为微生物二苯并恶氮平酮，但其生物活性从未被研究过。对海洋三萜西酚A的研究发现，其过氢苯并西平系统是介导其与Brk结合的关键药效团。DA与sipholenol A - perhydrobenzoxepine的生物等构相似性激发了DA与潜在Brk结合的分子对接模拟。研究了DA对多种前列腺癌（PC）细胞系的抗增殖作用，包括LNCaP（去势/激素敏感原发性腺癌）、PC3和22Rv1（去势抵抗），以及雄激素不依赖型DU145细胞。LNCaP细胞对DA的影响最为敏感，其次是PC3， IC50值分别为7.6 μM和9.8 μM。DA处理显著降低LNCaP细胞的迁移和克隆原性。Western blot分析显示，DA能够以剂量依赖性的方式降低两种细胞系中活化的Brk、FAK和STAT3的表达水平。DA也降低了总FAK的表达水平，但不影响Brk的总表达水平，而总STAT3的表达水平仅在LNCaP细胞中受到抑制。这些结果突出了DA通过靶向Brk-FAK-STAT3轴抑制PC增殖和迁移的作用。DA是一种潜在的原型，可以特别用于表达brk的PC控制。
{"title":"Demethylmycemycin A, a dibenzoxazepinone from the marine-derived Dactylosporangium sp. OK1079, with prostate cancer suppressive effects via targeting BRK-FAK-STAT3 axis","authors":"Marwa Elsbaey, Md Towhidul Islam Tarun, Radwan Alnajjar, Takahiro Jomori, Junichi Tanaka, Naoya Oku, Khalid El Sayed, Yasuhiro Igarashi","doi":"10.1038/s41429-025-00871-2","DOIUrl":"10.1038/s41429-025-00871-2","url":null,"abstract":"Breast tumor kinase (Brk) is an intracellular kinase that initiates a downstream oncogenic signaling through phosphorylation of focal adhesion kinase (FAK) and signal transducer and activator of transcription 3 (STAT3). Demethylmycemycin A (DA) was isolated from a sponge-derived Dactylosporangium sp. OK1079. Though known as a microbial dibenzoxazepinone, its biological activity has never been investigated. Previous studies on the marine triterpene sipholenol A identified its perhydrobenzoxepine system as the key pharmacophore that mediated its Brk binding. The bioisosteric similarity of DA to the sipholenol A perhydrobenzoxepine motivated a molecular docking simulation of DA for potential Brk binding. The antiproliferative effect of DA was investigated against diverse prostate cancer (PC) cell lines including LNCaP (castration/hormone-sensitive primary adenocarcinoma), PC3, and 22Rv1 (castration-resistant), in addition to the androgen-independent DU145 cells. LNCaP cells were the most sensitive to the effects of DA, followed by PC3, showing IC50 values of 7.6 and 9.8 μM, respectively. DA treatments significantly reduced the migration and clonogenicity of the LNCaP cells. Western blot analysis indicated the ability of DA to reduce the expression levels of activated Brk, FAK and STAT3 in a dose-dependent manner in both cell lines. DA also decreased the expression levels of the total FAK but didn’t affect the total level of Brk while the expression level of total STAT3 was only suppressed in LNCaP cells. These results highlight the PC proliferation and migration suppressive effects of DA through targeting Brk-FAK-STAT3 axis. DA is a potential prototype hit that can be developed particularly for Brk-expressing PC control.","PeriodicalId":54884,"journal":{"name":"Journal of Antibiotics","volume":"79 1","pages":"1-14"},"PeriodicalIF":2.7,"publicationDate":"2025-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145460353","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 : 2025-11-07DOI: 10.1038/s41429-025-00878-9
Amina Hayat, Aalia Khanem, Ikram Ullah, Muhammad Riaz, Farhan Younas
Antibiotics have transformed the treatment of bacterial infections, but their efficacy is increasingly threatened by antimicrobial resistance (AMR). Resistance mechanisms, such as target site modification, efflux pumps, and porin loss, necessitate alternative strategies, including the use of non-antibiotic adjuvants. This study evaluated the synergistic effects of non-steroidal anti-inflammatory drugs (NSAIDs) combined with antibiotics on the antimicrobial susceptibility of multidrug-resistant Escherichia coli. Clinical E. coli strains were exposed to antibiotics (ciprofloxacin, tetracycline, ampicillin) with or without NSAIDs (acetylsalicylic acid, ibuprofen). Antibiotic susceptibility was assessed via disk diffusion, while minimum inhibitory/bactericidal concentrations (MICs/MBCs) were determined to quantify interactions. Membrane integrity was evaluated through cytoplasmic contents release assays. NSAIDs significantly enhanced antibiotic susceptibility, reducing MICs/MBCs in most strains. Membrane leakage assays demonstrated increased release of intracellular components, suggesting compromised membrane integrity. The strongest synergy was observed with ciprofloxacin-ibuprofen combinations. NSAIDs potentiate antibiotic activity against resistant E. coli, likely through membrane disruption. This adjuvant approach could help combat AMR and warrants further investigation.
{"title":"Reversion of multidrug resistance in clinical isolates of Escherichia coli using non-steroidal anti-inflammatory drugs (NSAIDs)","authors":"Amina Hayat, Aalia Khanem, Ikram Ullah, Muhammad Riaz, Farhan Younas","doi":"10.1038/s41429-025-00878-9","DOIUrl":"10.1038/s41429-025-00878-9","url":null,"abstract":"Antibiotics have transformed the treatment of bacterial infections, but their efficacy is increasingly threatened by antimicrobial resistance (AMR). Resistance mechanisms, such as target site modification, efflux pumps, and porin loss, necessitate alternative strategies, including the use of non-antibiotic adjuvants. This study evaluated the synergistic effects of non-steroidal anti-inflammatory drugs (NSAIDs) combined with antibiotics on the antimicrobial susceptibility of multidrug-resistant Escherichia coli. Clinical E. coli strains were exposed to antibiotics (ciprofloxacin, tetracycline, ampicillin) with or without NSAIDs (acetylsalicylic acid, ibuprofen). Antibiotic susceptibility was assessed via disk diffusion, while minimum inhibitory/bactericidal concentrations (MICs/MBCs) were determined to quantify interactions. Membrane integrity was evaluated through cytoplasmic contents release assays. NSAIDs significantly enhanced antibiotic susceptibility, reducing MICs/MBCs in most strains. Membrane leakage assays demonstrated increased release of intracellular components, suggesting compromised membrane integrity. The strongest synergy was observed with ciprofloxacin-ibuprofen combinations. NSAIDs potentiate antibiotic activity against resistant E. coli, likely through membrane disruption. This adjuvant approach could help combat AMR and warrants further investigation.","PeriodicalId":54884,"journal":{"name":"Journal of Antibiotics","volume":"79 2","pages":"110-121"},"PeriodicalIF":2.7,"publicationDate":"2025-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145472486","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 : 2025-10-28DOI: 10.1038/s41429-025-00873-0
Md. Mehebub Al Raji, Naoya Oku, Toshihiko Nogawa, Agus Trianto, Yasuhiro Igarashi
Litchficin (1), a new acyloin, and three known metabolites, N-succinylanthranilic acid (2), kurasoin A (3), and soraphinol B (4), were isolated from a coral-derived halophilic Gram-positive bacterium, Litchfieldia sp. TUR-22. Compounds 1–4 at 10 µg ml−1 suppressed the radicle elongation of lettuce seeds to 38–56% of nontreated seeds.
{"title":"Litchficin, a germination inhibitory acyloin from a halophilic Gram-positive bacterium of the genus Litchfieldia","authors":"Md. Mehebub Al Raji, Naoya Oku, Toshihiko Nogawa, Agus Trianto, Yasuhiro Igarashi","doi":"10.1038/s41429-025-00873-0","DOIUrl":"10.1038/s41429-025-00873-0","url":null,"abstract":"Litchficin (1), a new acyloin, and three known metabolites, N-succinylanthranilic acid (2), kurasoin A (3), and soraphinol B (4), were isolated from a coral-derived halophilic Gram-positive bacterium, Litchfieldia sp. TUR-22. Compounds 1–4 at 10 µg ml−1 suppressed the radicle elongation of lettuce seeds to 38–56% of nontreated seeds.","PeriodicalId":54884,"journal":{"name":"Journal of Antibiotics","volume":"79 1","pages":"61-65"},"PeriodicalIF":2.7,"publicationDate":"2025-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145379747","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 : 2025-10-16DOI: 10.1038/s41429-025-00870-3
Saba Ghaffari, Maryam Esmaeili, Marjan Mohammadi
Helicobacter pylori infection is widely prevalent and can lead to peptic ulcer disease and gastric cancer. Treatment is challenged by a growing rate of antibiotic resistance. In this study, we evaluated the efficacy of olorofim (F901318), a DHODH inhibitor against Aspergillus fumigatus, in targeting H. pylori. The minimum inhibitory concentration (MIC) of olorofim against H. pylori reference and three multiple drug-resistant strains was determined. The nature of its growth inhibitory effect was assessed using liquid and solid bacterial culture. The general toxicity of olorofim was assessed against other bacteria and reassessed against eukaryotic cells. The effect of olorofim on DHODH activity was tested using a substrate reduction assay. Pairwise sequence alignment was carried out on H. pylori and A. fumigatus DHODH amino acid sequences. The MIC of olorofim against H. pylori reference strain and three MDR strains ranged from 0.075 to 0.625 µg mL−1. The growth-inhibitory effect was demonstrated to be bactericidal. Olorofim showed no general toxicity against other tested bacteria and was further confirmed to be non-toxic to eukaryotic cells. However, olorofim did not inhibit the activity of the recombinant H. pylori DHODH enzyme. Accordingly, sequence alignment revealed that four of the critical olorofim-binding residues in A. fumigatus DHODH differ in H. pylori. Olorofim demonstrated a strong bactericidal effect against H. pylori, making it a promising drug candidate for treating antibiotic-resistant cases. However, both our experimental findings and sequence analysis suggest that the DHODH enzyme in H. pylori is unlikely to be the molecular target of this drug candidate.
{"title":"Olorofim, a potential novel drug candidate against Helicobacter pylori infection","authors":"Saba Ghaffari, Maryam Esmaeili, Marjan Mohammadi","doi":"10.1038/s41429-025-00870-3","DOIUrl":"10.1038/s41429-025-00870-3","url":null,"abstract":"Helicobacter pylori infection is widely prevalent and can lead to peptic ulcer disease and gastric cancer. Treatment is challenged by a growing rate of antibiotic resistance. In this study, we evaluated the efficacy of olorofim (F901318), a DHODH inhibitor against Aspergillus fumigatus, in targeting H. pylori. The minimum inhibitory concentration (MIC) of olorofim against H. pylori reference and three multiple drug-resistant strains was determined. The nature of its growth inhibitory effect was assessed using liquid and solid bacterial culture. The general toxicity of olorofim was assessed against other bacteria and reassessed against eukaryotic cells. The effect of olorofim on DHODH activity was tested using a substrate reduction assay. Pairwise sequence alignment was carried out on H. pylori and A. fumigatus DHODH amino acid sequences. The MIC of olorofim against H. pylori reference strain and three MDR strains ranged from 0.075 to 0.625 µg mL−1. The growth-inhibitory effect was demonstrated to be bactericidal. Olorofim showed no general toxicity against other tested bacteria and was further confirmed to be non-toxic to eukaryotic cells. However, olorofim did not inhibit the activity of the recombinant H. pylori DHODH enzyme. Accordingly, sequence alignment revealed that four of the critical olorofim-binding residues in A. fumigatus DHODH differ in H. pylori. Olorofim demonstrated a strong bactericidal effect against H. pylori, making it a promising drug candidate for treating antibiotic-resistant cases. However, both our experimental findings and sequence analysis suggest that the DHODH enzyme in H. pylori is unlikely to be the molecular target of this drug candidate.","PeriodicalId":54884,"journal":{"name":"Journal of Antibiotics","volume":"79 1","pages":"41-49"},"PeriodicalIF":2.7,"publicationDate":"2025-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145304393","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 prevalence of multidrug-resistant (MDR) gram-positive bacteria, including methicillin-resistant Staphylococcus aureus (MRSA) and linezolid-resistant Enterococcus faecalis, highlights the critical demand for new antibacterial agents that target resistance pathways. BB-Cl-Amidine is originally considered as a peptidyl arginine deiminase inhibitor and till now, its potential antimicrobial activity has not been explored. This study sought to evaluate the antibacterial effectiveness and underlying mechanisms of BB-Cl-Amidine against MDR gram-positive pathogens. The results showed that BB-Cl-Amidine exhibited potent antibacterial activity with minimum inhibitory concentration (MIC) values ranging from 25 μM to 50 μM against MRSA, E. faecalis and various of Gram-positive bacteria clinical isolates. At sub-MIC concentrations, BB-Cl-Amidine significantly reduced biofilm formation in both S. aureus and E. faecalis. Moreover, the increased permeability and depolarizing membrane potential of S. aureus was found by BB-Cl-Amidine. The antibacterial activity of BB-Cl-Amidine can be neutralized by cardiolipin (CL) and phosphatidylglycerol (PG). Furthermore, BB-Cl-Amidine exposure resulted in the abnormal expression of functional proteins correlated with the cell membranes and phospholipid metabolas. In summary, the potential antibacterial and anti-biofilm activities of BB-Cl-Amidine are demonstrated via membrane disruption, offering a promising scaffold for combating MDR Gram-positive infections.
{"title":"Antibacterial effects of BB-Cl-Amidine against multidrug-resistant Gram-positive pathogens via membrane disruption","authors":"Zhenfeng Wang, Junhua Ma, Jintuan Lin, Congcong Li, Yong Xiang, Zhijian Yu, Bing Bai, Guiqiu Li, Ying Wei","doi":"10.1038/s41429-025-00869-w","DOIUrl":"10.1038/s41429-025-00869-w","url":null,"abstract":"The escalating prevalence of multidrug-resistant (MDR) gram-positive bacteria, including methicillin-resistant Staphylococcus aureus (MRSA) and linezolid-resistant Enterococcus faecalis, highlights the critical demand for new antibacterial agents that target resistance pathways. BB-Cl-Amidine is originally considered as a peptidyl arginine deiminase inhibitor and till now, its potential antimicrobial activity has not been explored. This study sought to evaluate the antibacterial effectiveness and underlying mechanisms of BB-Cl-Amidine against MDR gram-positive pathogens. The results showed that BB-Cl-Amidine exhibited potent antibacterial activity with minimum inhibitory concentration (MIC) values ranging from 25 μM to 50 μM against MRSA, E. faecalis and various of Gram-positive bacteria clinical isolates. At sub-MIC concentrations, BB-Cl-Amidine significantly reduced biofilm formation in both S. aureus and E. faecalis. Moreover, the increased permeability and depolarizing membrane potential of S. aureus was found by BB-Cl-Amidine. The antibacterial activity of BB-Cl-Amidine can be neutralized by cardiolipin (CL) and phosphatidylglycerol (PG). Furthermore, BB-Cl-Amidine exposure resulted in the abnormal expression of functional proteins correlated with the cell membranes and phospholipid metabolas. In summary, the potential antibacterial and anti-biofilm activities of BB-Cl-Amidine are demonstrated via membrane disruption, offering a promising scaffold for combating MDR Gram-positive infections.","PeriodicalId":54884,"journal":{"name":"Journal of Antibiotics","volume":"79 1","pages":"30-40"},"PeriodicalIF":2.7,"publicationDate":"2025-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145260199","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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