Article
Chemistry, Organic
Fan Zhang, Rene F. Ramos Alvarenga, Kurt Throckmorton, Shaurya Chanana, Doug R. Braun, Jen Fossen, Miao Zhao, Sue McCrone, Mary Kay Harper, Scott R. Rajski, Warren E. Rose, David R. Andes, Michael G. Thomas, Tim S. Bugni
Summary: In this study, a novel marine-derived siderophore, Pseudonochelin (1), was discovered using genome mining and metabolomics technologies. It was found that 1 contained a previously unidentified 5-aminosalicylic acid unit. Through annotation of a putative biosynthetic gene cluster and bioinformatics analysis, the biosynthesis of 1 was proposed. Furthermore, 1 exhibited iron-dependent antibacterial activity both in vitro and in vivo.
Article
Biotechnology & Applied Microbiology
Jacob M. Wurlitzer, Aleksa Stanisic, Ina Wasmuth, Sandra Jungmann, Dagmar Fischer, Hajo Kries, Markus Gressler
Summary: This study reports the biosynthesis of cyclic pentapeptides in Mortierella alpina, highlighting early-diverging fungi as an underestimated resource of natural products. The enzymes involved in this biosynthesis are more closely related to bacterial NRPSs, suggesting a bacterial origin of these NRPS genes in Mortierella. This discovery establishes early-diverging fungi as prolific natural compound producers and sheds light on the origin of their biosynthetic capacity.
APPLIED AND ENVIRONMENTAL MICROBIOLOGY
(2021)
Article
Multidisciplinary Sciences
Thomas J. Booth, Kenan A. J. Bozhueyuek, Jonathon D. Liston, Sibyl F. D. Batey, Ernest Lacey, Barrie Wilkinson
Summary: The article explores the evolutionary biosynthesis of antibiotics and shows how gene duplication and neo-functionalization can lead to pathway bifurcation, allowing for testing of new structures and recovery of old structures through gene loss.
NATURE COMMUNICATIONS
(2022)
Review
Biochemistry & Molecular Biology
Sara Martin-Villanueva, Gabriel Gutierrez, Dieter Kressler, Jesus de la Cruz
Summary: Ubiquitin is a highly conserved small protein in eukaryotes that functions as a post-translational modifier through ubiquitination. It plays a crucial role in ribosome biogenesis and function, along with other ubiquitin-like proteins such as SUMO. The fusion of ubiquitin moieties to specific ribosomal proteins is evolutionarily significant and helps regulate cellular processes.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Article
Microbiology
Eunji Kim, Young Eun Du, Yeon Hee Ban, Yern-Hyerk Shin, Dong-Chan Oh, Yeo Joon Yoon
Summary: OMS A displays greater potency against Mycobacterium tuberculosis and human cancer cells compared to OMS B, with substrate promiscuous adenylation domain in the second module of OMS synthetase playing a key role in the synthesis process.
FRONTIERS IN MICROBIOLOGY
(2021)
Article
Multidisciplinary Sciences
Arthur A. Melo, Thiemo Sprink, Jeffrey K. Noel, Elena Vazquez-Sarandeses, Chris van Hoorn, Saif Mohd, Justus Loerke, Christian M. T. Spahn, Oliver Daumke
Summary: In this study, the researchers used cryo-electron tomography to determine the membrane-bound structure of EHD4, providing insights into its membrane binding and oligomerization mode.
NATURE COMMUNICATIONS
(2022)
Article
Biotechnology & Applied Microbiology
Panpan Han, Zhou Chen, Yangliu Liu, Aijin Ma, Siting Li, Yingmin Jia
Summary: This study revealed the reason for the production of multi-component brevilaterin in Brevibacillus laterosporus and identified key design sites to enhance specificity. The findings provide a reasonable direction for genetic engineering and contribute to a deeper understanding of the adenylation domain. This could lead to more accurate and efficient design and utilization of brevilaterins, as well as applications in biotechnology.
MICROBIAL CELL FACTORIES
(2022)
Article
Biochemistry & Molecular Biology
Zhi-Wen Li, Bai Ruan, Pei-Jun Yang, Jing-Jing Liu, Ping Song, Juan-Li Duan, Lin Wang
Summary: This study identified the LSEC-specific hallmark genes Oit3 and Dnase1l3 by comparing the marker genes of liver endothelial cells (ECs) and liver capillary ECs. The Oit3-CreERT2-tdTomato mouse model was constructed, which showed specific expression in the liver and validated the identity of LSECs. This research provides a valuable model for studying the complexities of LSECs in liver diseases.
SIGNAL TRANSDUCTION AND TARGETED THERAPY
(2023)
Article
Infectious Diseases
Yan Chen, Yanqin Tu, Tingyu Pan, Zixin Deng, Lian Duan
Summary: Dithiolopyrrolone antibiotics have well-known biological activities, but the biosynthesis mechanism of the characteristic bicyclic scaffold is still unknown. In this study, the adenylation domain of a multi-domain non-ribosomal peptide synthase DtpB from the biosynthetic gene cluster of thiolutin was found to not only recognize and adenylate cysteine, but also play a crucial role in peptide bond formation. Additionally, an eight-membered ring compound was discovered as an intermediate during the formation of the bicyclic structure. These findings propose a new biosynthesis mechanism for the bicyclic scaffold of dithiolopyrrolones and reveal additional functions of the adenylation domain.
Article
Biochemistry & Molecular Biology
Angela H. Soeriyadi, Sarah E. Ongley, Jan-Christoph Kehr, Russel Pickford, Elke Dittmann, Brett A. Neilan
Summary: The study found that the marine cyanobacterial nonribosomal peptide synthetase (NRPS) pathway is amenable for the biosynthesis of indolactam variants, with relaxed specificity observed in the native lyngbyatoxin pathway NRPS. Site-directed mutagenesis of the substrate-binding pocket resulted in altered substrate preference, showing relative congruence between in vitro substrate activation and in vivo product formation. Further research with alternative tailoring domains may reveal the true in vivo effects of the mutations introduced.
Article
Multidisciplinary Sciences
Stefanie Mueller, Johanna Bialas, Stella V. Ryu, Nicola V. Catone, Annette V. Aichem
Summary: The ubiquitin-like modifier FAT10 is upregulated in inflammatory conditions and promotes the degradation of conjugated substrates through the 26S proteasome. The HECT-type ubiquitin E3 ligase HUWE1 is found to be FAT10ylated and targeted for proteasomal degradation. Additionally, the autophagy-related protein AMBRA1 is identified as a new interaction partner of FAT10, suggesting a potential interplay between all three proteins in cellular processes.
Article
Biotechnology & Applied Microbiology
Miguel C. Santoscoy, Laura R. Jarboe
Summary: The economic viability of bioprocesses is limited by the operating conditions tolerated by the cell factory. Engineering the microbial cell membrane can increase robustness and expand the production capacity. In this study, we produced cholesterol-like molecules using squalene hopene cyclase (SHC) and observed increased tolerance to chemicals and improved membrane trafficking processes. This engineering approach significantly increased the production titers for wax-esters and ethanol.
METABOLIC ENGINEERING
(2022)
Article
Biochemistry & Molecular Biology
Masaki Miyaguchi, Yoichi Nakanishi, Andres D. Maturana, Kimihiko Mizutani, Tomoaki Niimi
Summary: This study reveals the changes in the interaction between the Robo2 ectodomain and NELL1/2 under acidic conditions, as well as the impact of alternative splicing isoforms of Robo2 on the conformation of the hairpin-like structure and the binding affinity with NELL1/2.
JOURNAL OF MOLECULAR BIOLOGY
(2022)
Article
Biotechnology & Applied Microbiology
Sandra Haas, Monika Desombre, Frank Kirschhoefer, Matthias C. Huber, Stefan M. Schiller, Juergen Hubbuch
Summary: This manuscript investigates the purification protocols for an elastin-like protein (ELP) and evaluates their scalability and performance. The study finds that immobilized metal ion affinity chromatography (IMAC) achieves the highest purity and lowest nucleic acid contamination, while salt-induced precipitation offers a fast and simple alternative for large-scale production. Additional inverse transition cycling (ITC) purification leads to the highest purity but requires expensive temperature-dependent centrifugation steps.
FRONTIERS IN BIOENGINEERING AND BIOTECHNOLOGY
(2022)
Article
Biochemistry & Molecular Biology
Joshua C. Corpuz, Ashay Patel, Tony D. Davis, Larissa M. Podust, J. Andrew McCammon, Michael D. Burkart
Summary: This study reveals the binding specificities between peptidyl carrier proteins (PCPs) and adenylation (A) domains in non-ribosomal peptide synthetases (NRPSs) using chemical biology approaches. The research also demonstrates the possibility of controlling PCP binding specificity through modifying interfacial interactions.
ACS CHEMICAL BIOLOGY
(2022)
Article
Chemistry, Medicinal
Nishad Thamban Chandrika, Emily K. Dennis, Katelyn R. Brubaker, Stefan Kwiatkowski, David S. Watt, Sylvie Garneau-Tsodikova
Summary: Fluorinated aryl- and heteroaryl-substituted monohydrazones demonstrate excellent broad-spectrum activity against various fungal strains, including clinically relevant Candida auris strains. These compounds exhibit fungicidal activity with low hemolysis and no mammalian cell cytotoxicity, prevent biofilm formation, and do not induce resistance in C. auris over multiple passages.
Article
Chemistry, Medicinal
Soo-Kyoung Kim, Huy X. Ngo, Emily K. Dennis, Nishad Thamban Chandrika, Philip DeShong, Sylvie Garneau-Tsodikova, Vincent T. Lee
Summary: Pseudomonas aeruginosa infection in cystic fibrosis patients leads to excessive production of alginate, blocking the airways. Ebselen and its analogues were found to inhibit alginate production, suggesting a potential treatment option for patients infected with mucoid P. aeruginosa in the future.
ACS INFECTIOUS DISEASES
(2021)
Article
Chemistry, Medicinal
Keith D. Green, Allan H. Pang, Nishad Thamban Chandrika, Atefeh Garzan, Anthony D. Baughn, Oleg Tsodikov, Sylvie Garneau-Tsodikova
Summary: Antimicrobial drug resistance is a global health issue that results in hundreds of thousands of deaths annually. This study identified novel compounds with potent antibacterial activity against Staphylococcus aureus, including methicillin-resistant strains, with minimum inhibitory concentration as low as 1 μM. Some of these compounds also showed inhibitory effect against nontubercular mycobacteria, and were nontoxic to mammalian cells at relevant concentrations.
ACS INFECTIOUS DISEASES
(2022)
Article
Chemistry, Medicinal
Allan H. Pang, Keith D. Green, Nishad Thamban Chandrika, Atefeh Garzan, Ankita Punetha, Selina Y. L. Holbrook, Melisa J. Willby, James E. Posey, Oleg V. Tsodikov, Sylvie Garneau-Tsodikova
Summary: Eis acetyltransferase is a clinically significant mechanism of tuberculosis resistance to kanamycin. Inhibitors of Eis have been discovered, which can effectively abolish resistance to kanamycin in highly resistant strains. Additionally, several compounds with toxic effects on mycobacteria have been identified, with a mechanism of toxicity distinct from Eis inhibition.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Biochemistry & Molecular Biology
Skye Travis, Keith D. Green, Nathaniel C. Gilbert, Oleg Tsodikov, Sylvie Garneau-Tsodikova, Matthew K. Thompson
Summary: The Gram-positive pathogen Staphylococcus aureus is a major cause of antimicrobial resistance related deaths worldwide. Inhibiting the FosB enzyme can restore the activity of fosfomycin and increase the effectiveness of this antibiotic.
Article
Biochemistry & Molecular Biology
Allan H. Pang, Keith D. Green, Ankita Punetha, Nishad Thamban Chandrika, Kaitlind C. Howard, Sylvie Garneau-Tsodikova, Oleg Tsodikov
Summary: In this study, it was found that five existing drugs (azelastine, venlafaxine, chloroquine, mefloquine, and proguanil) can serve as inhibitors of Mycobacterium tuberculosis, a causative agent of TB. Among them, a proguanil analogue designed based on the Eis-proguanil complex was found to be more potent. These findings provide a starting point for further development of Eis inhibitors.
Article
Chemistry, Medicinal
Kaitlind C. Howard, Sylvie Garneau-Tsodikova
Summary: This study reports the design, synthesis, and selective antibacterial activity of 14 novel third-generation ZAF derivatives against P. gingivalis. These compounds displayed superior/selective antibacterial activity, bactericidal effects, inhibition of biofilm growth, no hemolytic activity, and lower cytotoxicity against mammalian cells compared to ZAF.
JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Chemistry, Medicinal
Keith D. Green, Nishad Thamban Chandrika, Loan Y. Vu, Allan H. Pang, Oleg V. Tsodikov, Sylvie Garneau-Tsodikova
Summary: The emergence of multidrug-resistant bacteria and the poor efficacy of available antibiotics have led to the urgent need for novel antibiotics. In this study, we synthesized a series of 46 aromatic hydrazides as potential treatments for A. baumannii infections. 34 compounds showed low-to sub-mu M inhibitory effects on A. baumannii growth and demonstrated high potency against multidrug-resistant clinical isolates, while being non-toxic to mammalian cells. These compounds have the potential to be developed into a selective anti-A. baumannii antibiotic.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Review
Mycology
Abbygail C. Spencer, Katelyn R. Brubaker, Sylvie Garneau-Tsodikova
Summary: Systemic fungal infections are increasing, especially in immunocompro-mised and post-surgical patients. This has led to the increased use of antifungal agents, resulting in escalating resistance rates. However, there is a lack of novel antifungal agents to combat this problem. This review discusses the current situation of antifungal agents and explores potential agents in development.
FUNGAL BIOLOGY REVIEWS
(2023)
Article
Biochemistry & Molecular Biology
Sarah L. Price, Derek Thibault, Taylor M. Garrison, Amanda Brady, Haixun Guo, Thomas E. Kehl-Fie, Sylvie Garneau-Tsodikova, Robert D. Perry, Tim van Opijnen, Matthew B. Lawrenz
Summary: Nutritional immunity involves limiting the availability of essential transition metals to invading pathogens. Yersinia pestis, the causative agent of plague, secretes a molecule called yersiniabactin to acquire iron and zinc during infection. This study identified the mechanism of yersiniabactin secretion, which has remained elusive for over 30 years, and demonstrated its importance for bacterial virulence.
Article
Biochemistry & Molecular Biology
Nishad Thamban Chandrika, Keith D. Green, Abbygail C. Spencer, Oleg V. Tsodikov, Sylvie Garneau-Tsodikova
Summary: Novel substituted monohydrazides synthesized for this study demonstrated broad-spectrum activity against different fungal strains, including clinically relevant Candida auris strains. These compounds showed comparable or superior activity to amphotericin B against most of the tested fungal strains, along with fungistatic activity and no mammalian cell toxicity. They also inhibited the formation of fungal biofilms, and no resistance was developed by Candida albicans ATCC 10231 (strain A) even after repeated exposures.
RSC MEDICINAL CHEMISTRY
(2023)
Article
Biochemistry & Molecular Biology
Skye Travis, Keith D. Green, Nishad Thamban Chandrika, Allan H. Pang, Patrick A. Frantom, Oleg V. Tsodikov, Sylvie Garneau-Tsodikova, Matthew K. Thompson
Summary: Antimicrobial resistance is a major threat to human health worldwide, and one of the common mechanisms is the production of antibiotic-modifying enzymes like FosB. This study identified eight potential inhibitors of FosB enzyme in Staphylococcus aureus through high-throughput screening and characterized their structures and inhibition kinetics. The results provide valuable insights for future design of FosB inhibitors.
RSC MEDICINAL CHEMISTRY
(2023)
Review
Biochemistry & Molecular Biology
Evan T. Miller, Oleg V. Tsodikov, Sylvie Garneau-Tsodikova
Summary: This review provides a comprehensive overview of dimethylallyl tryptophan synthase (DMATS) prenyltransferases (PTs), covering their structure-function relationships, engineering applications, and mechanistic understanding. It summarizes key findings and lessons learned from studies conducted over the past 14 years (2009-2023), while also identifying current gaps in our knowledge about these enzymes. The review highlights the accumulated knowledge about the unique properties and capabilities of DMATS-type PTs as promising biocatalysts.
NATURAL PRODUCT REPORTS
(2023)
Article
Multidisciplinary Sciences
Sarah L. Price, Viveka Vadyvaloo, Jennifer K. DeMarco, Amanda Brady, Phoenix A. Gray, Thomas E. Kehl-Fie, Sylvie Garneau-Tsodikova, Robert D. Perry, Matthew B. Lawrenz
Summary: Research has shown that the iron-scavenging siderophore Ybt produced by Yersinia pestis not only helps overcome iron-mediated nutritional immunity, but may also contribute to overcoming zinc-mediated nutritional immunity. Furthermore, it was discovered that Ybt competes with calprotectin for zinc during Y. pestis infection, aiding the bacteria in overcoming zinc limitation. Additionally, Ybt assists in surmounting zinc limitation within the flea midgut, serving as a bona fide zinc acquisition mechanism for Y. pestis during infection of both mammalian and insect hosts.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2021)
Review
Biochemistry & Molecular Biology
Kaitlind C. Howard, Octavio A. Gonzalez, Sylvie Garneau-Tsodikova
Summary: Periodontal diseases are inflammatory diseases caused by pathogenic bacteria, and current antibacterial treatment options may harm beneficial bacterial species in the oral microbiome. The development of more effective and specific antibacterial agents is needed to control oral pathogens in a polymicrobial environment, including natural product isolation and synthetic methods.
RSC MEDICINAL CHEMISTRY
(2021)
