Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0038187 (starvation)
 24,951 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Shigella flexneri strains were assayed for the ability to synthesize and utilize phenolate and hydroxamate siderophores. The hydroxamate aerobactin was synthesized by all isolates tested, whereas phenolates were only rarely produced. Expression of aerobactin was accompanied by production of a single iron-regulated outer membrane protein (Mr = 74,000). This protein was not produced by a mutant defective in aerobactin utilization and may serve as the aerobactin receptor. Phenolate (enterobactin)-producing strains synthesized three additional outer membrane proteins (Mr = 74,000, 81,000, and 83,000) in response to iron starvation. These proteins are the same apparent size as those produced by Escherichia coli K-12 strains. Ent sequences are apparently present in strains which do not synthesize this compound. Although normally silent, ent genes can be activated in Ent- strains to produce Ent+ variants. These laboratory variants are phenotypically indistinguishable from clinical Ent+ isolates.
 ...
PMID:Expression of hydroxamate and phenolate siderophores by Shigella flexneri. 622 75

Rabbits are not usually susceptible to intestinal Shigella infection without extensive pretreatment, including starvation and administration of antimicrobial, antimotility, and toxic agents (carbon tetrachloride). Most animals infected this way die rapidly and do not always develop colonic lesions and signs of dysentery. We describe here a successful experimental infection in the adult rabbit which does not require preparatory treatment and which reproduced characteristic features of human shigellosis. Unstarved, untreated adult rabbits were infected by direct inoculation of virulent Shigella flexneri 2a (10 ml of 10(7) bacteria per ml) into the proximal colon after ligation of the distal cecum (cecal bypass). Within 24 h of infection, most inoculated animals consistently developed clinical dysentery, characterized by liquid stool mixed with mucus and blood, leukocytosis, anorexia, and weight loss. Histologically, there were edema, exudation, superficial ulceration, and polymorphonuclear infiltrations in the lamina propria; crypt abscess formation; focal hemorrhages; and the presence of immunohistochemically stained S. flexneri in the colonic mucosa. Successful bacterial colonization was indicated by the isolation of the challenge strain of S. flexneri 2a from the colonic contents. None of the control rabbits challenged with nonvirulent S. flexneri or without cecal bypass developed dysentery or colitis. We conclude that successful Shigella infection can be induced by direct colonic inoculation with virulent S. flexneri 2a in adult rabbits without starvation and pretreatment. The colitis is dependent on the virulence of the bacteria and on the cecal bypass. This model should be useful in studies of the immunopathogenesis of Shigella infection.
 ...
PMID:Development of an improved animal model of shigellosis in the adult rabbit by colonic infection with Shigella flexneri 2a. 759 Oct 70

DNA polymerase II (Pol II) is regulated as part of the SOS response to DNA damage in Escherichia coli. We examined the participation of Pol II in the response to oxidative damage, adaptive mutation, and recombination. Cells lacking Pol II activity (polB delta 1 mutants) exhibited 5- to 10-fold-greater sensitivity to mode 1 killing by H2O2 compared with isogenic polB+ cells. Survival decreased by about 15-fold when polB mutants containing defective superoxide dismutase genes, sodA and sodB, were compared with polB+ sodA sodB mutants. Resistance to peroxide killing was restored following P1 transduction of polB cells to polB+ or by conjugation of polB cells with an F' plasmid carrying a copy of polB+. The rate at which Lac+ mutations arose in Lac- cells subjected to selection for lactose utilization, a phenomenon known as adaptive mutation, was increased threefold in polB backgrounds and returned to wild-type rates when polB cells were transduced to polB+. Following multiple passages of polB cells or prolonged starvation, a progressive loss of sensitivity to killing by peroxide was observed, suggesting that second-site suppressor mutations may be occurring with relatively high frequencies. The presence of suppressor mutations may account for the apparent lack of a mutant phenotype in earlier studies. A well-established polB strain, a dinA Mu d(Apr lac) fusion (GW1010), exhibited wild-type (Pol II+) sensitivity to killing by peroxide, consistent with the accumulation of second-site suppressor mutations. A high titer anti-Pol II polyclonal antibody was used to screen for the presence of Pol II in other bacteria and in the yeast Saccharomyces cerevisiae. Cross-reacting material was found in all gram-negative strains tested but was not detected in gram-positive strains or in S. cerevisiae. Induction of Pol II by nalidixic acid was observed in E. coli K-12, B, and C, in Shigella flexneri, and in Salmonella typhimurium.
 ...
PMID:Involvement of Escherichia coli DNA polymerase II in response to oxidative damage and adaptive mutation. 792 92

We have isolated two transposon insertion mutations of the pst-phoU operon which result in the constitutive expression of the phoA gene product, alkaline phosphatase. The two mutations also render Escherichia coli invasive towards cultured HEp-2 cells and define a novel Pho-regulated invasion pathway. The presence of the large 'invasion' plasmid derived from an entero-invasive E. coli (EIEC) clinical isolate in these mutants leads to enhanced invasiveness toward cultured HEp-2 cells, a phenomenon referred to as the 'hyper-invasive' phenotype. Transduction of a pst-phoU insertion mutation into clinical isolates of EIEC and Shigella flexneri results in constitutive PhoA expression and coupled hyper-invasiveness in the former but not the latter. We speculate that the Pho-regulated invasion pathway described here, while silent in bacteria grown in standard laboratory rich media, may become functional in the host when invasive bacteria encounter nutrient starvation and/or other related stress conditions.
 ...
PMID:Hyper-invasive mutants define a novel Pho-regulated invasion pathway in Escherichia coli. 793 62

Inorganic polyphosphate (poly P) is a chain of tens or many hundreds of phosphate (Pi) residues linked by high-energy phosphoanhydride bonds. Despite inorganic polyphosphate's ubiquity--found in every cell in nature and likely conserved from prebiotic times--this polymer has been given scant attention. Among the reasons for this neglect of poly P have been the lack of sensitive, definitive, and facile analytical methods to assess its concentration in biological sources and the consequent lack of demonstrably important physiological functions. This review focuses on recent advances made possible by the introduction of novel, enzymatically based assays. The isolation and ready availability of Escherichia coli polyphosphate kinase (PPK) that can convert poly P and ADP to ATP and of a yeast exopolyphosphatase that can hydrolyze poly P to Pi, provide highly specific, sensitive, and facile assays adaptable to a high-throughput format. Beyond the reagents afforded by the use of these enzymes, their genes, when identified, mutated, and overexpressed, have offered insights into the physiological functions of poly P. Most notably, studies in E. coli reveal large accumulations of poly P in cellular responses to deficiencies in an amino acid, Pi, or nitrogen or to the stresses of a nutrient downshift or high salt. The ppk mutant, lacking PPK and thus severely deficient in poly P, also fails to express RpoS (a sigma factor for RNA polymerase), the regulatory protein that governs > or = 50 genes responsible for stationary-phase adaptations to resist starvation, heat and oxidant stresses, UV irradiation, etc. Most dramatically, ppk mutants die after only a few days in stationary phase. The high degree of homology of the PPK sequence in many bacteria, including some of the major pathogenic species (e.g. Mycobacterium tuberculosis, Neisseria meningitidis, Helicobacter pylori, Vibrio cholerae, Salmonella typhimurium, Shigella flexneri, Pseudomonas aeruginosa, Bordetella pertussis, and Yersinia pestis), has prompted the knockout of their ppk gene to determine the dependence of virulence on poly P and the potential of PPK as a target for antimicrobial drugs. In yeast and mammalian cells, exo- and endopolyphosphatases have been identified and isolated, but little is known about the synthesis of poly P or its physiologic functions. Whether microbe or human, all species depend on adaptations in the stationary phase, which is truly a dynamic phase of life. Most research is focused on the early and reproductive phases of organisms, which are rather brief intervals of rapid growth. More attention needs to be given to the extensive period of maturity. Survival of microbial species depends on being able to manage in the stationary phase. In view of the universality and complexity of basic biochemical mechanisms, it would be surprising if some of the variety of poly P functions observed in microorganisms did not apply to aspects of human growth and development, to aging, and to the aberrations of disease. Of theoretical interest regarding poly P is its antiquity in prebiotic evolution, which along with its high energy and phosphate content, make it a plausible precursor to RNA, DNA, and proteins. Practical interest in poly P includes many industrial applications, among which is the microbial removal of Pi in aquatic environments.
 ...
PMID:Inorganic polyphosphate: a molecule of many functions. 1087 45

The importance of inorganic polyphosphate (poly P) and poly P kinase (PPK), the enzyme principally responsible for its synthesis, has been established previously for stationary-phase survival of Escherichia coli and virulence in Pseudomonas aeruginosa. The gene (ppk) that encodes PPK is highly conserved among many bacterial pathogens, including Shigella and Salmonella spp. In view of the phylogenetic similarity of the enteropathogens and the frequency with which virulence factors are expressed in stationary phase, the ppk gene of pathogenic Shigella flexneri, Salmonella enterica serovar Dublin, and Salmonella enterica serovar typhimurium have been cloned and deleted. In some of these mutants lacking ppk, the phenotypes included features indicative of decreased virulence such as: (i) growth defects, (ii) defective responses to stress and starvation, (iii) loss of viability, (iv) polymyxin sensitivity, (v) intolerance to acid and heat, and (vi) diminished invasiveness in epithelial cells. Thus PPK may prove, as it has with P. aeruginosa, to be an attractive target for antibiotics, with low toxicity because PPK is not found in higher eukaryotes.
 ...
PMID:Inorganic polyphosphate is essential for long-term survival and virulence factors in Shigella and Salmonella spp. 1203 42

Global proteomic analysis was performed with Shigella flexneri strain 2457T in association with three distinct growth environments: S. flexneri growing in broth (in vitro), S. flexneri growing within epithelial cell cytoplasm (intracellular), and S. flexneri that were cultured with, but did not invade, Henle cells (extracellular). Compared to in vitro and extracellular bacteria, intracellular bacteria had increased levels of proteins required for invasion and cell-to-cell spread, including Ipa, Mxi, and Ics proteins. Changes in metabolic pathways in response to the intracellular environment also were evident. There was an increase in glycogen biosynthesis enzymes, altered expression of sugar transporters, and a reduced amount of the carbon storage regulator CsrA. Mixed acid fermentation enzymes were highly expressed intracellularly, while tricarboxylic acid (TCA) cycle oxidoreductive enzymes and most electron transport chain proteins, except CydAB, were markedly decreased. This suggested that fermentation and the CydAB system primarily sustain energy generation intracellularly. Elevated levels of PntAB, which is responsible for NADPH regeneration, suggested a shortage of reducing factors for ATP synthesis. These metabolic changes likely reflect changes in available carbon sources, oxygen levels, and iron availability. Intracellular bacteria showed strong evidence of iron starvation. Iron acquisition systems (Iut, Sit, FhuA, and Feo) and the iron starvation, stress-associated Fe-S cluster assembly (Suf) protein were markedly increased in abundance. Mutational analysis confirmed that the mixed-acid fermentation pathway was required for wild-type intracellular growth and spread of S. flexneri. Thus, iron stress and changes in carbon metabolism may be key factors in the S. flexneri transition from the extra- to the intracellular milieu.
...
PMID:Analysis of the proteome of intracellular Shigella flexneri reveals pathways important for intracellular growth. 2410 89

Antibiotic resistance/tolerance has become a severe threat to human and animal health. To combat antibiotic-resistant/tolerant bacteria, it is of significance to improve the efficacy of traditional antibiotics. Here we show that indole potentiates tobramycin to kill stationary-phase Staphylococcus aureus cells after a short, combined treatment, with its derivative 5-methylindole being the most potent compound tested and with the absence of ions as a prerequisite. Consistently, this combined treatment also kills various types of S. aureus persister cells as induced by the protonophore CCCP, nutrient shift, or starvation, as well as methicillin-resistant S. aureus (MRSA) cells. Importantly, 5-methylindole potentiates tobramycin killing of S. aureus persisters in a mouse acute skin wound model. Furthermore, 5-methylindole facilitates killing of many strains of gram-positive pathogens such as Staphylococcus epidermidis, Enterococcus faecalis, and Streptococcus pyogenes by aminoglycoside antibiotics, whereas it suppresses the action of aminoglycoside against the gram-negative pathogens Escherichia coli and Shigella flexneri. In conclusion, our work may pave the way for the development of indole derivatives as adjuvants to potentiate aminoglycosides against gram-positive pathogens.
 ...
PMID:5-Methylindole Potentiates Aminoglycoside Against Gram-Positive Bacteria Including Staphylococcus aureus Persisters Under Hypoionic Conditions. 3218 44