scholarly journals Polyphosphate Kinase 2 (PPK2) Enzymes: Structure, Function, and Roles in Bacterial Physiology and Virulence

2022 ◽  
Vol 23 (2) ◽  
pp. 670
Author(s):  
Nolan Neville ◽  
Nathan Roberge ◽  
Zongchao Jia
Keyword(s):  
Molecular Chaperone ◽  
Bacterial Infections ◽  
Pathogenic Bacteria ◽  
Bacterial Virulence ◽  
Polyphosphate Kinase ◽  
Biological Functions ◽  
Inorganic Polyphosphate ◽  
Bacterial Physiology ◽  
Enzyme Families ◽  
Phosphorus Storage

Inorganic polyphosphate (polyP) has been implicated in an astonishing array of biological functions, ranging from phosphorus storage to molecular chaperone activity to bacterial virulence. In bacteria, polyP is synthesized by polyphosphate kinase (PPK) enzymes, which are broadly subdivided into two families: PPK1 and PPK2. While both enzyme families are capable of catalyzing polyP synthesis, PPK1s preferentially synthesize polyP from nucleoside triphosphates, and PPK2s preferentially consume polyP to phosphorylate nucleoside mono- or diphosphates. Importantly, many pathogenic bacteria such as Pseudomonas aeruginosa and Acinetobacter baumannii encode at least one of each PPK1 and PPK2, suggesting these enzymes may be attractive targets for antibacterial drugs. Although the majority of bacterial polyP studies to date have focused on PPK1s, PPK2 enzymes have also begun to emerge as important regulators of bacterial physiology and downstream virulence. In this review, we specifically examine the contributions of PPK2s to bacterial polyP homeostasis. Beginning with a survey of the structures and functions of biochemically characterized PPK2s, we summarize the roles of PPK2s in the bacterial cell, with a particular emphasis on virulence phenotypes. Furthermore, we outline recent progress on developing drugs that inhibit PPK2 enzymes and discuss this strategy as a novel means of combatting bacterial infections.

scholarly journals Hsp100 Molecular Chaperone ClpB and Its Role in Virulence of Bacterial Pathogens

2021 ◽  
Vol 22 (10) ◽  
pp. 5319
Author(s):  
Sabina Kędzierska-Mieszkowska ◽  
Michal Zolkiewski
Keyword(s):  
Oxidative Stress ◽  
Molecular Chaperone ◽  
Bacterial Infections ◽  
Pathogenic Bacteria ◽  
Biological Function ◽  
Bacterial Pathogens ◽  
Cellular Proteins ◽  
Induced Stresses ◽  
Aaa Atpases ◽  
And Oxidative Stress

This review focuses on the molecular chaperone ClpB that belongs to the Hsp100/Clp subfamily of the AAA+ ATPases and its biological function in selected bacterial pathogens, causing a variety of human infectious diseases, including zoonoses. It has been established that ClpB disaggregates and reactivates aggregated cellular proteins. It has been postulated that ClpB’s protein disaggregation activity supports the survival of pathogenic bacteria under host-induced stresses (e.g., high temperature and oxidative stress), which allows them to rapidly adapt to the human host and establish infection. Interestingly, ClpB may also perform other functions in pathogenic bacteria, which are required for their virulence. Since ClpB is not found in human cells, this chaperone emerges as an attractive target for novel antimicrobial therapies in combating bacterial infections.

scholarly journals Structural characterisation of a polyphosphate kinase

2014 ◽  
Vol 70 (a1) ◽  
pp. C466-C466
Author(s):  
Alice Loasby ◽  
Peter Roach ◽  
Petra Oyston
Keyword(s):  
Pathogenic Bacteria ◽  
Bacterial Species ◽  
Exothermic Reaction ◽  
Stringent Response ◽  
Titration Calorimetry ◽  
Polyphosphate Kinase ◽  
Inorganic Polyphosphate ◽  
Structural Characterisation ◽  
Signalling Molecules ◽  
Expression Of Genes

When deprived of nutrients bacteria undergo what is referred to as the `stringent response'. During the stringent response, the cell induces the expression of genes to cope with stress and starvation and diverts resources away from cell growth and division. This involves altering the cellular levels of the signalling molecules: ppGpp, pppGpp and inorganic polyphosphate (polyP)[1]. This is controlled by four enzymes; Polyphosphate kinase (Ppk), Exopolyphosphatase (Ppx), RelA and SpoT. Therefore, modulation of these enzymes is an attractive method for targeting pathogenic bacteria such as Francisella tularensis (F. tularensis), the causative agent of tularemia. FtPpk transfers phosphate from polyP to ADP to generate ATP, a reaction that is fully reversible. The importance of FtPpk in infection has been demonstrated in knockout mutants which resulted in defective growth of F. tularensis in macrophages[2]. Mutagenesis in other pathogenic bacteria has yielded attenuated mutants, suggesting an important role for Ppk in a broad spectrum of bacterial species[3]. To maximise our understanding of FtPpk, our aim was to obtain co-crystals of the enzyme and substrates. Isothermal Titration Calorimetry (ITC) was used to measure the binding of polyP and ADP to FtPpk as independent substrates. FtPpk binds ADP very weakly or not at all in the absence of polyP. FtPpk binds polyP in an exothermic reaction with a relatively high affinity (0.385 µM) in the absence of ADP. Co-crystals of FtPpk with polyP and ADP have been obtained and optimised to diffract to 2.0 Å, identifying a potential binding site for polyP. A non-hydrolysable analogue of ATP has been chemically synthesised to allow co-crystallisation experiments.

scholarly journals Bacteriophage adherence to mucus mediates preventive protection against pathogenic bacteria

2019 ◽  
Author(s):  
Gabriel MF Almeida ◽  
Elina Laanto ◽  
Roghaieh Ashrafi ◽  
Lotta-Riina Sundberg
Keyword(s):  
Bacterial Infections ◽  
Pathogenic Bacteria ◽  
Phage Therapy ◽  
Bacterial Virulence ◽  
Model Systems ◽  
Symbiotic Relationship ◽  
Flavobacterium Columnare ◽  
Ecological Interactions ◽  
Fish Pathogen ◽  
Mucosal Surfaces

AbstractMetazoan mucosal surfaces are major interfaces between the organism and environment. These surfaces have been proposed to host bacteriophages in a symbiotic relationship with metazoans. Considering the so far poorly understood phage–mucus interaction and its role in ecological interactions and for mucosal bacterial infections, empirical evidence and model systems need to be established. Here, using the fish pathogenFlavobacterium columnareand rainbow trout (Oncorhynchus mykiss), we show that phages infecting the pathogen are capable of binding to primary mucus layers and protecting fish from infections. Furthermore, exposure to mucus changes the bacterial phenotype by increasing bacterial virulence and susceptibility to phage infections. Tests using other phage–bacterium pairs suggest that the relevance of mucus for bacteria and phages may be widespread in the biosphere. Therefore, interactions of bacteria and phages inside the mucus environment may be important for disease and evolution, and this phenomenon has significant potential to be exploited for preventive phage therapy approaches.

scholarly journals Bacteriophage Adherence to Mucus Mediates Preventive Protection against Pathogenic Bacteria

mBio ◽  
2019 ◽  
Vol 10 (6) ◽  
Author(s):  
Gabriel M. F. Almeida ◽  
Elina Laanto ◽  
Roghaieh Ashrafi ◽  
Lotta-Riina Sundberg
Keyword(s):  
Disease Ecology ◽  
Bacterial Infections ◽  
Pathogenic Bacteria ◽  
Phage Therapy ◽  
Bacterial Virulence ◽  
Model Systems ◽  
Symbiotic Relationship ◽  
Content Type ◽  
Ecological Benefit ◽  
Mucosal Surfaces

ABSTRACT Metazoans were proposed to host bacteriophages on their mucosal surfaces in a symbiotic relationship, where phages provide an external immunity against bacterial infections and the metazoans provide phages a medium for interacting with bacteria. However, scarce empirical evidence and model systems have left the phage-mucus interaction poorly understood. Here, we show that phages bind both to porcine mucus and to rainbow trout (Oncorhynchus mykiss) primary mucus, persist up to 7 days in the mucosa, and provide protection against Flavobacterium columnare. Also, exposure to mucus changes the bacterial phenotype by increasing bacterial virulence and susceptibility to phage infections. This trade-off in bacterial virulence reveals ecological benefit of maintaining phages in the metazoan mucosal surfaces. Tests using other phage-bacterium pairs suggest that phage binding to mucus may be widespread in the biosphere, indicating its importance for disease, ecology, and evolution. This phenomenon may have significant potential to be exploited in preventive phage therapy. IMPORTANCE The mucosal surfaces of animals are habitat for microbes, including viruses. Bacteriophages—viruses that infect bacteria—were shown to be able to bind to mucus. This may result in a symbiotic relationship in which phages find bacterial hosts to infect, protecting the mucus-producing animal from bacterial infections in the process. Here, we studied phage binding on mucus and the effect of mucin on phage-bacterium interactions. The significance of our research is in showing that phage adhesion to mucus results in preventive protection against bacterial infections, which will serve as basis for the development of prophylactic phage therapy approaches. Besides, we also reveal that exposure to mucus upregulates bacterial virulence and that this is exploited by phages for infection, adding one additional layer to the metazoan-bacterium-phage biological interactions and ecology. This phenomenon might be widespread in the biosphere and thus crucial for understanding mucosal diseases, their outcome and treatment.

Probiotics Slow the Growth of Pathogenic Bacteria

2019 ◽  
Vol 14 (1) ◽  
pp. 28-31 ◽  
Author(s):  
Rowles H. L.
Keyword(s):  
Growth Rate ◽  
Bacterial Infections ◽  
Pathogenic Bacteria ◽  
Diarrheal Disease ◽  
Growth Curves ◽  
Mortality Rates ◽  
Controlled Delivery ◽  
E Coli ◽  
Multiple Strains ◽  
Commercial Probiotics

Probiotics are live microorganisms, which when ingested in sufficient amounts, confer health benefits to the host by improving the gut microflora balance. The purpose of this research was to determine whether commercial probiotic products containing multitude of commensal bacteria would reduce the growth rate of pathogenic bacteria, specifically Escherichia coli and Salmonella typhimurium. Growth curves were established, and the growth rates were compared for samples of E. coli, S. typhimurium, Nature’s Bounty Controlled Delivery probiotic, Sundown Naturals Probiotic Balance probiotic, and cocultures of the pathogenic bacteria mixed with the probiotics. The findings of this research were that the commercial probiotics significantly reduced the growth rate of E. coli and S. typhimurium when combined in cocultures. Probiotics containing multiple strains may be taken prophylactically to reduce the risk of bacterial infections caused by E. coli and S. typhimurium. Probiotics could be used to reduce the high global morbidity and mortality rates of diarrheal disease.

Bacterial Polyphosphate Kinases Revisited: Role in Pathogenesis and Therapeutic Potential

2019 ◽  
Vol 20 (3) ◽  
pp. 292-301 ◽  
Author(s):  
Lalit Kumar Gautam ◽  
Prince Sharma ◽  
Neena Capalash
Keyword(s):  
Drug Target ◽  
Bacterial Infections ◽  
Therapeutic Potential ◽  
Wide Distribution ◽  
Medical Community ◽  
Polyphosphate Kinase ◽  
Potential Drug Target ◽  
Potential Drug ◽  
Resistant Strains ◽  
Structural Aspects

Bacterial infections have always been an unrestrained challenge to the medical community due to the rise of multi-drug tolerant and resistant strains. Pioneering work on Escherichia coli polyphosphate kinase (PPK) by Arthur Kornberg has generated great interest in this polyphosphate (PolyP) synthesizing enzyme. PPK has wide distribution among pathogens and is involved in promoting pathogenesis, stress management and susceptibility to antibiotics. Further, the absence of a PPK orthologue in humans makes it a potential drug target. This review covers the functional and structural aspects of polyphosphate kinases in bacterial pathogens. A description of molecules being designed against PPKs has been provided, challenges associated with PPK inhibitor design are highlighted and the strategies to enable development of efficient drug against this enzyme have also been discussed.

scholarly journals Bacteriophages as drivers of bacterial virulence and their potential for biotechnological exploitation

2020 ◽  
Author(s):  
Kaat Schroven ◽  
Abram Aertsen ◽  
Rob Lavigne
Keyword(s):  
Small Molecules ◽  
Bacterial Infections ◽  
Bacterial Virulence ◽  
Arms Race ◽  
Control Mechanisms ◽  
Human Pathogens ◽  
Vaccine Candidates ◽  
Cargo Proteins ◽  
Genes Encoding ◽  
Mutualistic Relationship

ABSTRACT Bacteria-infecting viruses (phages) and their hosts maintain an ancient and complex relationship. Bacterial predation by lytic phages drives an ongoing phage-host arms race, whereas temperate phages initiate mutualistic relationships with their hosts upon lysogenization as prophages. In human pathogens, these prophages impact bacterial virulence in distinct ways: by secretion of phage-encoded toxins, modulation of the bacterial envelope, mediation of bacterial infectivity and the control of bacterial cell regulation. This review builds the argument that virulence-influencing prophages hold extensive, unexplored potential for biotechnology. More specifically, it highlights the development potential of novel therapies against infectious diseases, to address the current antibiotic resistance crisis. First, designer bacteriophages may serve to deliver genes encoding cargo proteins which repress bacterial virulence. Secondly, one may develop small molecules mimicking phage-derived proteins targeting central regulators of bacterial virulence. Thirdly, bacteria equipped with phage-derived synthetic circuits which modulate key virulence factors could serve as vaccine candidates to prevent bacterial infections. The development and exploitation of such antibacterial strategies will depend on the discovery of other prophage-derived, virulence control mechanisms and, more generally, on the dissection of the mutualistic relationship between temperate phages and bacteria, as well as on continuing developments in the synthetic biology field.

scholarly journals AMPK activates Parkin independent autophagy and improves post sepsis immune defense against secondary bacterial lung infections

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Nathaniel B. Bone ◽  
Eugene J. Becker ◽  
Maroof Husain ◽  
Shaoning Jiang ◽  
Anna A. Zmijewska ◽  
...  
Keyword(s):  
Bacterial Infections ◽  
Pathogenic Bacteria ◽  
Inflammatory Responses ◽  
Abdominal Sepsis ◽  
Immune Defense ◽  
Bacterial Killing ◽  
Lung Infections ◽  
Sepsis Survivors ◽  
The Impact

AbstractMetabolic and bioenergetic plasticity of immune cells is essential for optimal responses to bacterial infections. AMPK and Parkin ubiquitin ligase are known to regulate mitochondrial quality control mitophagy that prevents unwanted inflammatory responses. However, it is not known if this evolutionarily conserved mechanism has been coopted by the host immune defense to eradicate bacterial pathogens and influence post-sepsis immunosuppression. Parkin, AMPK levels, and the effects of AMPK activators were investigated in human leukocytes from sepsis survivors as well as wild type and Park2−/− murine macrophages. In vivo, the impact of AMPK and Parkin was determined in mice subjected to polymicrobial intra-abdominal sepsis and secondary lung bacterial infections. Mice were treated with metformin during established immunosuppression. We showed that bacteria and mitochondria share mechanisms of autophagic killing/clearance triggered by sentinel events that involve depolarization of mitochondria and recruitment of Parkin in macrophages. Parkin-deficient mice/macrophages fail to form phagolysosomes and kill bacteria. This impairment of host defense is seen in the context of sepsis-induced immunosuppression with decreased levels of Parkin. AMPK activators, including metformin, stimulate Parkin-independent autophagy and bacterial killing in leukocytes from post-shock patients and in lungs of sepsis-immunosuppressed mice. Our results support a dual role of Parkin and AMPK in the clearance of dysfunctional mitochondria and killing of pathogenic bacteria, and explain the immunosuppressive phenotype associated Parkin and AMPK deficiency. AMPK activation appeared to be a crucial therapeutic target for the macrophage immunosuppressive phenotype and to reduce severity of secondary bacterial lung infections and respiratory failure.

scholarly journals Cross-kingdom inhibition of bacterial virulence and communication by probiotic yeast metabolites

Microbiome ◽  
2021 ◽  
Vol 9 (1) ◽  
Author(s):  
Orit Malka ◽  
Dorin Kalson ◽  
Karin Yaniv ◽  
Reut Shafir ◽  
Manikandan Rajendran ◽  
...  
Keyword(s):  
Quorum Sensing ◽  
Gut Microbiome ◽  
Bacterial Infections ◽  
Pathogenic Bacteria ◽  
Molecular Mechanisms ◽  
Human Microbiome ◽  
Cell Communication ◽  
Probiotic Yeast ◽  
Gut Pathogen ◽  
Cell Cell

Abstract Background Probiotic milk-fermented microorganism mixtures (e.g., yogurt, kefir) are perceived as contributing to human health, and possibly capable of protecting against bacterial infections. Co-existence of probiotic microorganisms are likely maintained via complex biomolecular mechanisms, secreted metabolites mediating cell-cell communication, and other yet-unknown biochemical pathways. In particular, deciphering molecular mechanisms by which probiotic microorganisms inhibit proliferation of pathogenic bacteria would be highly important for understanding both the potential benefits of probiotic foods as well as maintenance of healthy gut microbiome. Results The microbiome of a unique milk-fermented microorganism mixture was determined, revealing a predominance of the fungus Kluyveromyces marxianus. We further identified a new fungus-secreted metabolite—tryptophol acetate—which inhibits bacterial communication and virulence. We discovered that tryptophol acetate blocks quorum sensing (QS) of several Gram-negative bacteria, particularly Vibrio cholerae, a prominent gut pathogen. Notably, this is the first report of tryptophol acetate production by a yeast and role of the molecule as a signaling agent. Furthermore, mechanisms underscoring the anti-QS and anti-virulence activities of tryptophol acetate were elucidated, specifically down- or upregulation of distinct genes associated with V. cholerae QS and virulence pathways. Conclusions This study illuminates a yet-unrecognized mechanism for cross-kingdom inhibition of pathogenic bacteria cell-cell communication in a probiotic microorganism mixture. A newly identified fungus-secreted molecule—tryptophol acetate—was shown to disrupt quorum sensing pathways of the human gut pathogen V. cholerae. Cross-kingdom interference in quorum sensing may play important roles in enabling microorganism co-existence in multi-population environments, such as probiotic foods and the gut microbiome. This discovery may account for anti-virulence properties of the human microbiome and could aid elucidating health benefits of probiotic products against bacterially associated diseases.

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