Molybdenum Enzymes and How They Support Virulence in Pathogenic Bacteria

Mononuclear molybdoenzymes are highly versatile catalysts that occur in organisms in all domains of life, where they mediate essential cellular functions such as energy generation and detoxification reactions. Molybdoenzymes are particularly abundant in bacteria, where over 50 distinct types of enzymes have been identified to date. In bacterial pathogens, all aspects of molybdoenzyme biology such as molybdate uptake, cofactor biosynthesis, and function of the enzymes themselves, have been shown to affect fitness in the host as well as virulence. Although current studies are mostly focused on a few key pathogens such as Escherichia coli, Salmonella enterica, Campylobacter jejuni, and Mycobacterium tuberculosis, some common themes for the function and adaptation of the molybdoenzymes to pathogen environmental niches are emerging. Firstly, for many of these enzymes, their role is in supporting bacterial energy generation; and the corresponding pathogen fitness and virulence defects appear to arise from a suboptimally poised metabolic network. Secondly, all substrates converted by virulence-relevant bacterial Mo enzymes belong to classes known to be generated in the host either during inflammation or as part of the host signaling network, with some enzyme groups showing adaptation to the increased conversion of such substrates. Lastly, a specific adaptation to bacterial in-host survival is an emerging link between the regulation of molybdoenzyme expression in bacterial pathogens and the presence of immune system-generated reactive oxygen species. The prevalence of molybdoenzymes in key bacterial pathogens including ESKAPE pathogens, paired with the mounting evidence of their central roles in bacterial fitness during infection, suggest that they could be important future drug targets.

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Bacteriophage can drive virulence in marine pathogens

Marine Disease Ecology ◽

10.1093/oso/9780198821632.003.0004 ◽

2020 ◽

pp. 73-82 ◽

Cited By ~ 1

Author(s):

Mark Little ◽

Maria Isabel Rojas ◽

Forest Rohwer

Keyword(s):

Pathogenic Bacteria ◽

Bacterial Pathogens ◽

Meta Analysis ◽

Relevant Literature ◽

Marine Ecosystems ◽

Marine Environments ◽

Human Pathogens ◽

Large Role ◽

Associated Bacteria ◽

And Function

The roles of prophages in disease have mainly considered human pathogens, while their role in marine pathogens has only recently been considered. This chapter reviews the relevant literature on what is known of prophages in marine ecosystems and provides a meta-analysis of the abundance and function of prophages in marine pathogenic bacteria. According to these results, bacterial pathogens in marine environments contain a significantly higher abundance of prophage DNA in their genomes than host-associated bacteria, which are non-pathogenic. The authors also surveyed the genetic content of the prophages that were associated with known pathogens and compared their functions to non-pathogens. Their findings suggest that horizontally acquired prophage-encoded DNA may play a large role in the ecology and evolution of marine diseases

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A Comparative Review on Current and Future Drug Targets Against Bacteria & Malaria

Current Drug Targets ◽

10.2174/1389450121666200129103618 ◽

2020 ◽

Vol 21 (8) ◽

pp. 736-775

Author(s):

Usha K. Rout ◽

A.S. Sanket ◽

Brijesh S. Sisodia ◽

Pradyumna K. Mohapatra ◽

Sanghamitra Pati ◽

...

Keyword(s):

Drug Resistance ◽

Infectious Diseases ◽

Drug Targets ◽

Pathogenic Bacteria ◽

Treatment Options ◽

Treatment Scenario ◽

Comparative Review ◽

Future Drug ◽

Life Threatening ◽

Novel Drug

Long before the discovery of drugs like ‘antibiotic and anti-parasitic drugs’, the infectious diseases caused by pathogenic bacteria and parasites remain as one of the major causes of morbidity and mortality in developing and underdeveloped countries. The phenomenon by which the organism exerts resistance against two or more structurally unrelated drugs is called multidrug resistance (MDR) and its emergence has further complicated the treatment scenario of infectious diseases. Resistance towards the available set of treatment options and poor pipeline of novel drug development puts an alarming situation. A universal goal in the post-genomic era is to identify novel targets/drugs for various life-threatening diseases caused by such pathogens. This review is conceptualized in the backdrop of drug resistance in two major pathogens i.e. “Pseudomonas aeruginosa” and “Plasmodium falciparum”. In this review, the available targets and key mechanisms of resistance of these pathogens have been discussed in detail. An attempt has also been made to analyze the common drug targets of bacteria and malaria parasite to overcome the current drug resistance scenario. The solution is also hypothesized in terms of a present pipeline of drugs and efforts made by scientific community.

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Long non-coding RNAs in regulation of adipogenesis and adipose tissue function

eLife ◽

10.7554/elife.59053 ◽

2020 ◽

Vol 9 ◽

Author(s):

Tiziana Squillaro ◽

Gianfranco Peluso ◽

Umberto Galderisi ◽

Giovanni Di Bernardo

Keyword(s):

Gene Expression ◽

Adipose Tissue ◽

Drug Targets ◽

Metabolic Diseases ◽

Tissue Development ◽

Cellular Functions ◽

Adipose Tissue Development ◽

And Function

Complex interaction between genetics, epigenetics, environment, and nutrition affect the physiological activities of adipose tissues and their dysfunctions, which lead to several metabolic diseases including obesity or type 2 diabetes. Here, adipogenesis appears to be a process characterized by an intricate network that involves many transcription factors and long noncoding RNAs (lncRNAs) that regulate gene expression. LncRNAs are being investigated to determine their contribution to adipose tissue development and function. LncRNAs possess multiple cellular functions, and they regulate chromatin remodeling, along with transcriptional and post-transcriptional events; in this way, they affect gene expression. New investigations have demonstrated the pivotal role of these molecules in modulating white and brown/beige adipogenic tissue development and activity. This review aims to provide an update on the role of lncRNAs in adipogenesis and adipose tissue function to promote identification of new drug targets for treating obesity and related metabolic diseases.

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From Genetic Footprinting to Antimicrobial Drug Targets: Examples in Cofactor Biosynthetic Pathways

Journal of Bacteriology ◽

10.1128/jb.184.16.4555-4572.2002 ◽

2002 ◽

Vol 184 (16) ◽

pp. 4555-4572 ◽

Cited By ~ 185

Author(s):

Svetlana Y. Gerdes ◽

Michael D. Scholle ◽

Mark D'Souza ◽

Axel Bernal ◽

Mark V. Baev ◽

...

Keyword(s):

Broad Spectrum ◽

Drug Targets ◽

Essential Gene ◽

Bacterial Pathogens ◽

Integrated Approach ◽

Cellular Functions ◽

Context Analysis ◽

E Coli ◽

Genetic Footprinting ◽

Gene Orthologs

ABSTRACT Novel drug targets are required in order to design new defenses against antibiotic-resistant pathogens. Comparative genomics provides new opportunities for finding optimal targets among previously unexplored cellular functions, based on an understanding of related biological processes in bacterial pathogens and their hosts. We describe an integrated approach to identification and prioritization of broad-spectrum drug targets. Our strategy is based on genetic footprinting in Escherichia coli followed by metabolic context analysis of essential gene orthologs in various species. Genes required for viability of E. coli in rich medium were identified on a whole-genome scale using the genetic footprinting technique. Potential target pathways were deduced from these data and compared with a panel of representative bacterial pathogens by using metabolic reconstructions from genomic data. Conserved and indispensable functions revealed by this analysis potentially represent broad-spectrum antibacterial targets. Further target prioritization involves comparison of the corresponding pathways and individual functions between pathogens and the human host. The most promising targets are validated by direct knockouts in model pathogens. The efficacy of this approach is illustrated using examples from metabolism of adenylate cofactors NAD(P), coenzyme A, and flavin adenine dinucleotide. Several drug targets within these pathways, including three distantly related adenylyltransferases (orthologs of the E. coli genes nadD, coaD, and ribF), are discussed in detail.

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Glycan:glycan interactions: High affinity biomolecular interactions that can mediate binding of pathogenic bacteria to host cells

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1421082112 ◽

2015 ◽

Vol 112 (52) ◽

pp. E7266-E7275 ◽

Cited By ~ 55

Author(s):

Christopher J. Day ◽

Elizabeth N. Tran ◽

Evgeny A. Semchenko ◽

Greg Tram ◽

Lauren E. Hartley-Tassell ◽

...

Keyword(s):

Protein Interactions ◽

Pathogenic Bacteria ◽

Dissociation Constants ◽

Bacterial Pathogens ◽

Bacterial Adherence ◽

Host Cells ◽

Cell Contact ◽

Diverse Range ◽

High Affinity ◽

Domains Of Life

Cells from all domains of life express glycan structures attached to lipids and proteins on their surface, called glycoconjugates. Cell-to-cell contact mediated by glycan:glycan interactions have been considered to be low-affinity interactions that precede high-affinity protein–glycan or protein–protein interactions. In several pathogenic bacteria, truncation of surface glycans, lipooligosaccharide (LOS), or lipopolysaccharide (LPS) have been reported to significantly reduce bacterial adherence to host cells. Here, we show that the saccharide component of LOS/LPS have direct, high-affinity interactions with host glycans. Glycan microarrays reveal that LOS/LPS of four distinct bacterial pathogens bind to numerous host glycan structures. Surface plasmon resonance was used to determine the affinity of these interactions and revealed 66 high-affinity host–glycan:bacterial–glycan pairs with equilibrium dissociation constants (KD) ranging between 100 nM and 50 µM. These glycan:glycan affinity values are similar to those reported for lectins or antibodies with glycans. Cell assays demonstrated that glycan:glycan interaction-mediated bacterial adherence could be competitively inhibited by either host cell or bacterial glycans. This is the first report to our knowledge of high affinity glycan:glycan interactions between bacterial pathogens and the host. The discovery of large numbers of glycan:glycan interactions between a diverse range of structures suggests that these interactions may be important in all biological systems.

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Broad spectrum antimicrobial activities from spore-forming bacteria isolated from the Vietnam Sea

PeerJ ◽

10.7717/peerj.10117 ◽

2020 ◽

Vol 8 ◽

pp. e10117

Author(s):

Khanh Minh Chau ◽

Dong Van Quyen ◽

Joshua M. Fraser ◽

Andrew T. Smith ◽

Thi Thu Hao Van ◽

...

Keyword(s):

Antimicrobial Activity ◽

Pathogenic Bacteria ◽

Antimicrobial Agents ◽

Bacterial Pathogens ◽

Paenibacillus Polymyxa ◽

Antimicrobial Activities ◽

Antimicrobial Compounds ◽

Antibiotic Resistant ◽

Future Drug ◽

Spore Forming Bacteria

The widespread occurrence of pathogenic bacteria resistant to last-line antibiotics has resulted in significant challenges in human and veterinary medicine. There is an urgent need for new antimicrobial agents that can be used to control these life threating pathogens. We report the identification of antimicrobial activities, against a broad range of bacterial pathogens, from a collection of marine-derived spore-forming bacteria. Although marine environments have been previously investigated as sources of novel antibiotics, studies on such environments are still limited and there remain opportunities for further discoveries and this study has used resources derived from an under-exploited region, the Vietnam Sea. Antimicrobial activity was assessed against a panel of Gram-positive and Gram-negative bacteria, including several multi-drug resistant pathogens. From a total of 489 isolates, 16.4% had antimicrobial activity. Of 23 shortlisted isolates with the greatest antimicrobial activity, 22 were Bacillus spp. isolates and one was a Paenibacillus polymyxa isolate. Most of the antimicrobial compounds were sensitive to proteases, indicating that they were proteins rather than secondary metabolites. The study demonstrated that marine bacteria derived from the Vietnam Sea represent a rich resource, producing antimicrobial compounds with activity against a broad range of clinically relevant bacterial pathogens, including important antibiotic resistant pathogens. Several isolates were identified that have particularly broad range activities and produce antimicrobial compounds that may have value for future drug development.

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Molecular characterization of SARS-CoV-2

Current Molecular Medicine ◽

10.2174/1566524020999201203213037 ◽

2020 ◽

Vol 20 ◽

Author(s):

Miribane Dërmaku-Sopjani ◽

Mentor Sopjani

Keyword(s):

Public Health ◽

Drug Targets ◽

Virus Genome ◽

Health Crisis ◽

Public Health Crisis ◽

Therapeutic Drugs ◽

New Public Health ◽

New Public ◽

And Function

Abstract:: The coronavirus disease 2019 (COVID-19) is currently a new public health crisis threatening the world. This pandemic disease is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The virus has been reported to be originated in bats and by yet unknown intermediary animals were transmitted to humans in China 2019. The SARSCoV- 2 spreads faster than its two ancestors the SARS-CoV and Middle East respiratory syndrome coronavirus (MERSCoV) but has reduced fatality. At present, the SARS-CoV-2 has caused about a 1.16 million of deaths with more than 43.4 million confirmed cases worldwide, resulting in a serious threat to public health globally with yet uncertain impact. The disease is transmitted by inhalation or direct contact with an infected person. The incubation period ranges from 1 to 14 days. COVID-19 is accompanied by various symptoms, including cough, fatigue. In most people the disease is mild, but in some other people, such as in elderly and people with chronic diseases, it may progress from pneumonia to a multi-organ dysfunction. Many people are reported asymptomatic. The virus genome is sequenced, but new variants are reported. Numerous biochemical aspects of its structure and function are revealed. To date, no clinically approved vaccines and/or specific therapeutic drugs are available to prevent or treat the COVID-19. However, there are reported intensive researches on the SARSCoV- 2 to potentially identify vaccines and/or drug targets, which may help to overcome the disease. In this review, we discuss recent advances in understanding the molecular structure of SARS-CoV-2 and its biochemical characteristics.

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Establishing a model to demonstrate physical and mathematical properties of chromatin fibres in fission yeast cells - Research in the Molecular Biophysics Lab at Hiroshima University

Impact ◽

10.21820/23987073.2018.3.89 ◽

2018 ◽

Vol 2018 (3) ◽

pp. 89-91

Author(s):

Shin-ichi Tate

Keyword(s):

Molecular Biology ◽

Yeast Cells ◽

Molecular Architecture ◽

Ministry Of Education ◽

Cellular Functions ◽

Sports Science ◽

Cellular Events ◽

And Function ◽

Education Culture ◽

Open The Doors

The field of molecular biology has provided great insights into the structure and function of key molecules. Thanks to this area of research, we can now grasp the biological details of DNA and have characterised an enormous number of molecules in massive data bases. These 'biological periodic tables' have allowed scientists to connect molecules to particular cellular events, furthering scientific understanding of biological processes. However, molecular biology has yet to answer questions regarding 'higher-order' molecular architecture, such as that of chromatin. Chromatin is the molecular material that serves as the building block for chromosomes, the structures that carry an organism's genetic information inside of the cell's nucleus. Understanding the physical properties of chromatin is crucial in developing a more thorough picture of how chromatin's structure relate to its key cellular functions. Moreover, by establishing a physical model of chromatin, scientists will be able to open the doors into the true inner workings of the cell nucleus. Professor Shin-ichi Tate and his team of researchers at Hiroshima University's Research Center for the Mathematics on Chromatin Live Dynamics (RcMcD), are attempting to do just that. Through a five-year grant funded by the Platform for Dynamic Approaches to Living Systems from the Ministry of Education, Culture, Sports, Science and Technology, Tate is aiming to gain a clearer understanding of the structure and dynamics of chromatin.

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Bend, Push, Stretch: Remarkable Structure and Mechanics of Single Intermediate Filaments and Meshworks

Cells ◽

10.3390/cells10081960 ◽

2021 ◽

Vol 10 (8) ◽

pp. 1960

Author(s):

K. Tanuj Sapra ◽

Ohad Medalia

Keyword(s):

Intermediate Filaments ◽

Eukaryotic Cell ◽

Coiled Coils ◽

Cellular Functions ◽

Mechanical Pressure ◽

Mechanical Feature ◽

Cellular Processes ◽

Nuclear Lamins ◽

Filament Networks ◽

And Function

The cytoskeleton of the eukaryotic cell provides a structural and functional scaffold enabling biochemical and cellular functions. While actin and microtubules form the main framework of the cell, intermediate filament networks provide unique mechanical properties that increase the resilience of both the cytoplasm and the nucleus, thereby maintaining cellular function while under mechanical pressure. Intermediate filaments (IFs) are imperative to a plethora of regulatory and signaling functions in mechanotransduction. Mutations in all types of IF proteins are known to affect the architectural integrity and function of cellular processes, leading to debilitating diseases. The basic building block of all IFs are elongated α-helical coiled-coils that assemble hierarchically into complex meshworks. A remarkable mechanical feature of IFs is the capability of coiled-coils to metamorphize into β-sheets under stress, making them one of the strongest and most resilient mechanical entities in nature. Here, we discuss structural and mechanical aspects of IFs with a focus on nuclear lamins and vimentin.

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Actin Cytoskeleton and Regulation of TGFβ Signaling: Exploring Their Links

Biomolecules ◽

10.3390/biom11020336 ◽

2021 ◽

Vol 11 (2) ◽

pp. 336

Author(s):

Roberta Melchionna ◽

Paola Trono ◽

Annalisa Tocci ◽

Paola Nisticò

Keyword(s):

Cancer Progression ◽

Transforming Growth Factor ◽

Transforming Growth Factor Β ◽

Tissue Homeostasis ◽

Actin Dynamics ◽

Human Tissues ◽

Cellular Functions ◽

Tgfβ Signaling ◽

Physical Mechanisms ◽

And Function

Human tissues, to maintain their architecture and function, respond to injuries by activating intricate biochemical and physical mechanisms that regulates intercellular communication crucial in maintaining tissue homeostasis. Coordination of the communication occurs through the activity of different actin cytoskeletal regulators, physically connected to extracellular matrix through integrins, generating a platform of biochemical and biomechanical signaling that is deregulated in cancer. Among the major pathways, a controller of cellular functions is the cytokine transforming growth factor β (TGFβ), which remains a complex and central signaling network still to be interpreted and explained in cancer progression. Here, we discuss the link between actin dynamics and TGFβ signaling with the aim of exploring their aberrant interaction in cancer.

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