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Eukaryon, Vol 3, February 2007, Lake Forest College Review Article Guts & Glory H. pylori: Cause of Peptic Ulcer

Ashley Johnson*, Bryan Kratz*, Lorraine Scanlon*,
Bicarbonate secretions, and reduce blood circulation and Alina Spivak*
which aids in cell renewal and repair. With the host’s defenses down, stomach acid can irritate the sensitive Gut Wrenching Diseases
Due to the 1983 discovery of H. pylori bacteria as
Peptic ulcers form on the epithelial cells of the stomach lining. An ulcer consists of two major structures: a understanding of the disease dramatically changed.
distinct ulcer margin and granulation tissue at the ulcer We now know that stress and spicy foods are not
base. A distinct ulcer margin is formed by the adjacent the leading causes of peptic ulcers. Symptoms
non-necrotic mucosa - the epithelial component. The including acute abdominal pain, vomiting of blood,
granulation tissue consists of fibroblasts, macrophages, and weight loss are characteristic of peptic ulcers.
and proliferating endothelial cells, which form Ulcers form because of the inflammation caused by
microvessels. On the molecular level, the pathogenesis H. pylori leading to sensitivity of gastric cells to the
of ulcer disease is believed to reflect an imbalance acid secreted by the infected patient’s stomach.
between increased corrosive stomach byproducts and Although more than half of the world’s population
decreased protective factors. As a result of stimulation is infected with H. pylori, most people remain
arising from the sight, smell, taste, or thought of food, asymptomatic. Current research suggests that
acetylcholine, a neurotransmitter, and gastrin, a several bacterial virulence genes such as CagA and
hormone, are released and act on the parietal cells to VacA, as well as the individual host’s genetic
produce acid. The mast cells in turn release histamine, predisposition,
influence
which also stimulates gastric acid secretion. In patients progression of disease. The mechanism of H. pylori
infected with H. pylori, the parietal cells have increased infection has been recently examined in detail
sensitivity to gastrin and possibly to histamine. The clarifying the morphological changes of the host
increased sensitivity causes corrosion of the stomach cell and how this promotes the formation of a
lining, leading to the formation of an ulcer (2). peptic ulcer. Present studies to explain the
persistence of H. pylori and propose how this
bacterium evolved key mechanisms to evade the
H. pylori trigger the host's immune system to release host’s immune response. Due to the advances in
immune response mediators. These molecules, such as the understanding of peptic ulcers, effective
reactive oxygen species and nitrogen made by treatments have been proposed to treat and
neutrophils, are released in the stomach and undergo eliminate this disease.
lysis due to low pH levels. These molecules can often damage DNA. Patients with gastric cancer often have constantly activated oncogenes, such as c-met, c-erbB- 2, K-sam, or inactivated tumor-suppressor genes, such In 1983, Australian scientists Robin Warren and Barry as p53, p16, and APC. Those affected also show Marshall showed that the leading cause of peptic ulcers abnormal alterations of genes implicated in cell is the infection of the stomach lining with a helical proliferation and apoptosis, such as cyclin D1, bcl-2, (spiral) shaped gram negative bacterium Helicobacter pylori (H. pylori). It was previously believed that peptic ulcers were caused by stress and consumption of spicy Not-So-Glorious Symptoms
One of the major symptoms of gastric ulcers is Characteristics
abdominal pain, which usually occurs during mealtimes as more acid is secreted into the stomach. H. pylori infection leads to inflammation of the gastric Hematemesis (vomiting of blood) is often seen in mucosa in 80% of peptic ulcer cases. H. pylori cause patients with gastric ulcers, which leads to a noticeable elevated acid secretion in people who develop reduction in the patient’s weight. Melena (i.e. foul duodenal ulcers, and decreased acid secretion in those smelling feces) is another symptom of gastric ulcers who develop gastric ulcers and gastric cancer (3, 5). that is often caused by the presence of oxidized iron Duodenal ulcers form due to acid hypersecretion in response to antral inflammation. In patients with gastric ulcers, H. pylori cause corpus inflammation which leads to decreased acid secretion and gastric atrophy (Figure A diet high in salt and lacking antioxidant vitamins might 1). Peptic ulcers are 0.3-0.4 cm in diameter in the promote low acid secretion and cause gastritis, which affected area of the stomach. The remaining 20% of leads to gastric ulcers and gastric cancer. Salt may peptic ulcer cases are caused by nonsteroidal anti- change acid secretion by suppressing parietal cells, inflammatory drugs (NSAIDS) like aspirin, which irritate causing gastric atrophy. Also, the antioxidant vitamins the stomach lining (3). NSAIDS hinder the protective in fresh fruit might protect specialized gastric cells from mechanisms of the stomach including mucus and reactive oxygen species released by inflammatory cells. Diet confirms why there is a high prevalence of ulcers in China and Japan. These countries not only have a high * This paper was written in BIO221 Cellular and Molecular Biology, taught by Dr. Shubhick DebBurman prevalence of H. pylori but also a traditionally salty diet.
h H.
H py
p l
y o
l r
o i
r
t ic antra
f ammation
Figure 1. H. pylori induced changes in stomach functioning lead to several gastrointestinal diseases Infection with H. pylori leads to
hypergastrinemia which may lead to inflammation depending on bacterial virulence, environmental factors, and host genetic differences.
Patients who develop inflammation of the gastric corpus exhibit decreased acid production which may lead to gastric cancer or gastric
ulcer. Those who maintain a healthy gastric corpus but have gastric antral inflammation exhibit increased acid production, which may lead
to duodenal ulcers.
Cigarette smoking also strongly predisposes to both of developing gastric carcinoma as a result of chronic You’ve “Gut” to Take These
VacA: Evacuate my body
The most effective treatment for peptic ulcers is a three The H. pylori vacuolating cytotoxin gene, vacA, is drug regimen consisting of a proton pump inhibitor naturally polymorphic. The two most diverse regions (PPI) and two antibiotics. Proton pump inhibitors work being are the signal region (which can be type s1 or s2) to expose H. pylori to the drug treatment. The most and the mid region (m1 or m2). The type s1/m1 and common antibiotic used is amoxicillin and the most s1/m2 strains of vacA are associated with peptic ulcer prevalent PPI is Omeprazole. Once the bacteria are and gastric cancer, whereas while the type s2/m2 eradicated by the drug regimen, the normal immune strains are non-toxic and associated with lower risk of response has the full potential to regenerate the peptic ulcer and gastric cancer. The features of vacA that determine the nontoxicity of these strains were determined by Letley et. al. (2003). They did this by Although a lot is already known about H. deleting parts of vacA and constructing isogenic hybrid pylori and the diseases it causes, there are four major strains in which regions of vacA were exchanged areas that are currently being expanded on. The fact between toxigenic and non-toxigenic strains. They that the bacterium resides in so many people yet showed that a naturally-occurring 12-amino acid symptoms of disease only appear in a few people is hydrophilic N-terminal extension found on intriguing. This question led researchers to investigate s2 VacA blocks vacuolating activity as while its removal whether bacterial virulence factors and differences in (making the strain s1-like) confers activity. They did the host attribute to this discrepancy. In addition, the chromosomal replacement of vaca in a nontoxigenic persistence of the bacterium in the infected individual strain with vacA from a toxigenic strain and found full suggests the possibility, addressed by current research, activating activity, proving that the vacoulation is that H. pylori evolved key mechanisms to evade the controlled entirely by elements within vacA. This host's immune responses. Studies of the molecular research defined why determined that H. pylori strains mechanism of the invasion of the gastric cells with H. with different vacA allelic structures have differing pylori have been elaborated upon in recent years. Also, new therapeutic agents and methods of treatment of gastrointestinal diseases have been proposed in Virulent Strain Carries CagA Gene
Another bacterial virulence factor is the polymorphism Disease or No Disease…That is the question
of the CagA protein. All H. pylori strains have the cagPAI DNA segment, but only some strains have the Current research suggests that several bacterial cagA gene that encodes the 145 -kDA CagA protein. virulence factors such as CagA and VacA genes, as These strains are called cagA+ strains, and while the well as the individual host’s genetic predisposition, strains lacking the cagA gene are called cagA-. The influence progression of H. pylori-related diseases. The cagA+ strains are more virulent than the cagA- strains World Health Organization recently has classified H. and are associated with gastric carcinoma. The CagA pylori as a class I carcinogen because of the risk factor is injected by the bacterium and subsequently associated binder 1 or growth factor receptor–bound protein 2. The H. pylori–induced motogenic response is phophatase, activates the phophatase activity, and suppressed and blocked by the inhibition of PLCγ and thereby induces morphological transformation of cells. of MAPK, respectively. Thus, upon translocation, CagA SHP-2 plays an important role in both cell growth and modulates cellular functions by deregulating c-Met cell motility. This morphological change is referred to receptor signaling. The activation of the motogenic as the hummingbird phenotype because the cell response in H. pylori–infected epithelial cells suggests undergoes dramatic elongation by means of the that CagA could be involved in tumor progression (8). attachment of cagA+. Higashi et. al. (2002) found that Western and East Asian CagA both contain tyrosine phosphorylation sites but they differ in structure. The primary response of the body to infection of H. pylori is inflammation. This is caused by the infiltration phosphorylation sites. The larger the number of binding of the gastric mucosa with neutrophils, macrophages, B cells, and T cells following release of interleukins. T phosphorylation, which leads to increased SHP-2 lymphocyte responses in acute H. pylori infection are binding and greater morphological changes. In predominantly of the CD4+ Th1 (mainly cell-mediated) contrast, the East Asian strains have a different tyrosine cell phenotype (3, 5). Although a seemingly large phosphorylation sequence at the region corresponding immune response is initiated, it is mostly ineffective, to the Western sequence that binds SHP-2 stronger because H. pylori bacteria are rarely completely and induces greater morphological changes to the cell eradicated from an infected individual. The persistence than the Western sequence, causing East Asian CagA of H. pylori and the high reinfection rate suggest that proteins to be more potent and leading to high gastric the host has significant anergy and is unable to build Interleukin-1 β  What alleles do you have?
VacA Does What?
Host genetic factors that affect interleukin-1-beta may Previous studies showed that VacA inhibits release of determine why some individuals affected with H. pylori IL-2 in Jurkat cells (human T-cell leukemia cells). This inhibition is linked to the ability of VacA to inactivate the Polymorphisms in human cytokine genes affect the Nuclear Factor of Activated T-cells (NFAT). This level of cytokine production by cells after contact with transcription factor is critical to the transcription of IL-2; H. pylori. Specific polymorphisms in the IL-1b gene and therefore, if VacA inactivates NFAT, IL-2 secretion is the IL-1 receptor-antagonist gene (IR-1RN) lead to inhibited, and Jurkat T cell proliferation is therefore increased gastric mucosal levels of IL-1b in individuals infected with H. pylori. IL-1b (interleukin-1-beta) is an However, Sundrud et al. (2004) propose that VacA has important pro-inflammatory cytokine and a powerful a different effect on primary human Th cells. Similar inhibitor of gastric acid secretion (5). The three testing with the human Th cells suggested that VacA reported diallelic polymorphisms in IL1B which have has only a modest effect on IL-2 secretion. VacA did been reported all represent C-to-T base transitions at not cause a reduction in IL-2 levels in either naïve or positions –511, -31, and +3954 basepairs from the memory Th cells. Therefore, it is now predicted that transcriptional start site. El-Omar et al., demonstrated VacA inhibits IL-2-driven proliferation of primary human that individuals who were carriers for of the interleukin-1 Th cells by a non-NFAT mechanism. Further studies beta- 31T allele had low acid secretion. The suggested that VacA suppresses cell cycle progression polymorphisms also increase the risk of gastric atrophy, in Th cells, similar to drugs such as rapamycin which hypochlorhydria, intestinal metaplasia, and gastric induce G1 arrest. Therefore, instead of blocking IL-2 cancer (5, 8). Using electrophoretic mobility shift secretion, and by that inhibiting Th cell proliferation in analysis to assess DNA binding in vitro, the interleukin- human Th cells, VacA might be blocking normal cell 1 beta -31T allele was associated with a five-fold cycle progression of these cells. Sundrud et al. found increase in DNA-binding after lipopolsaccharide that VacA must have an intact hydrophobic domain stimulation. Individuals carrying the interleukin-1 beta - within its N-terminal region. This component of VacA 31 T allele are more susceptible to developing structure is necessary for both inhibition of IL-2 hypochlorhydria, and subsequently gastric cancer, in secretion in Jurkat cells and inhibition of IL-2-driven the case of an infection by the bacterium H. pylori. proliferation of human primary Th cells. This region is Thus, the interleukin-1 beta gene is a crucial factor in attributed to making VacA anion-selective channels, determining if a person will develop gastric cancer (8). which may cause depolarization of the Th cell plasma membrane and lead to inhibition of IL-2- dependent T- Gastric Cancer
cell proliferation. Interestingly, a mutant VacA (VacA- (6-27) that completely lacks this entire hydrophobic region actually has a dominant negative effect and fully Helicobacter pylori is assumed to lead to invasive blocks the wildtype VacA mediated inhibition of T cell gastric cancer. H. pylori activate the hepatocyte growth proliferation both in Jurkat and primary human Th cells. factor/scatter factor receptor c-Met (oncogene), which is Thus, these scientists concluded that VacA has involved in invasive growth of tumor cells. The H. pylori immunosuppressive properties that help H.pylori evade effector protein CagA intracellularly targets the c-Met receptor and acts as an oncoprotein, promoting cellular processes that lead to changes in cell polarity, motility Treg Cells don’t regulate but promote disease
and differentiation. These changes may be related to the development of gastric cancer. CagA could Recent studies show that the host’s immune response represent a bacterial adaptor protein that associates often leads to immunopathology in an infected person with phospholipase Cγ (PCγ), but not with Grb2- (3, 5, 7). This conclusion stems from the fact that Th cells have a poor responsiveness to H. pylori antigens. H. pylori Learned to Avoid TLR
CD4+ T cells proliferate more during H. pylori infection in comparison to CD8+ T cells. Also, Lundgren et al. It is widely known that eukaryotic organisms have (2003) suggest that memory cells in infected individuals evolved many mechanisms to recognize bacterial proliferate a lot less in comparison to the memory cells agents so that a proper immune response can be of healthy individuals, and naïve cells barely proliferate activated to eradicate the bacterium. One such in either case. In fact, this difference in proliferation immunity are Toll-like receptors (TLRs), which rates of memory cells was nonexistent when both recognize components of bacterial membrane LPS and individuals were treated with another toxin (Tetanus- a bacterial protein flagellin that are released by many toxin). This implies that the reduced responsiveness of gram-negative bacteria. Gewirtz et al. (2004) suggested memory T cell proliferation in infected individuals was that although H. pylori contain both LPS and flagella, limited to H. pylori specific cells. This finding led to the they are still able to evade this immune response. The assumption that regulatory CD4+CD25high T cells (Treg scientists found that H. pylori releases much smaller cells) suppress proliferation of memory T-cells. Treg amounts of flagellin than other gram-negative bacteria cells are vital for controlling the immune response to and the flagellin that they do release is barely potent. The flagellin that is released does not play a large role responses. Therefore, it is currently suggested that in mediating proinflammatory gene expression in the repetitive stimulation of T cells with H. pylori antigen host. The usual effect of gram-negative bacteria is the may lead to activation of Treg cells that actively activation of TLR, which induces IL-8 secretion of a suppress the response of memory cells. Therefore, proinflammatory cytokine. However, H. pylori are able these authors showed that with prolonged infection, the to evade TLR mediated immunity by producing host’s own immunity activates H. pylori specific Treg impotent flagellin and preventing the release of this cells, which suppress memory cell proliferation potentially immunogenic, proinflammatory protein (15). CagA vs. Mucus
(COX) 4 Lowers Immune Response
CagA plays a major role in morphological changes Meyer et al. (2003) found that H. pylori induce induced by the Helicobacter pylori bacterium upon entry production of cyclooxygenase (COX) 4-2. COX is an of the gastric epithelial cells. Al-Mahroon et al. (2004) enzyme that is attributed to inhibition of epithelial preformed an experiment to test the effect of CagA (+) or CagA (-) strains of H. pylori on the mean gastric angiogenesis. Studies have shown that a byproduct of mucus thickness in humans when compared to an H. pylori, urease, allows the bacteria to survive the uninfected individual. Biopsies taken from each of the acidic pH of the stomach and also induces (COX) 4-2 patients were submitted to PCR to determine the expression (5, 13). (COX) 4-2 then produces presence of CagA (+). After staining and treating the prostaglandins such as prostaglandin E2 (PGE2) which biopsies, the mucus layer thickness was determined mediate inflammation. Therefore, the induction of using an integration of light microscopy, CCD camera, (COX) 4-2 by the host is a defense strategy that works and specific computer software. The results showed by making PGE2 that reduces inflammation. Also, that, on average, the mucus layer thickness was not Meyer et al. (2003) found that a decrease of affected in a manner that was statistically significant inflammation has been attributed to increased bacterial effectiveness of the host’s immune response leading to I SAID Drop Your Apical Junctions Now!
Another side effect of H. pylori infection is faulty apical Le+ H. pylori have an advantage
junctions and loss of cell-to-cell adhesion. Scientists wondered if CagA plays a role in the mediation of this Horizontal gene transfer and translational frame shifts effect and how it causes this abnormal morphological contribute to the large genetic diversity of this bacterium change. Bagnoli (2005) preformed an experiment in (5). Bergman et al (2005) showed that H. pylori which CagA and ZO-1(a known tight junction express Lewis blood group Antigen (Le) in their scaffolding protein) were tagged with antibodies so that lipopolysaccharide (LPS) that is phase variable, they could be easily seen under the microscope. The resulting in Le+ and Le- population of H. pylori within a results showed that in CagA expressing cells, the ZO-1 single strain. Similar to HIV, Le+ antigen of H. pylori protein was mislocated to the basolateral membrane variants can bind to the C-type lectin DC-SIGN and (Figure 2). It was also found that the apical junction present on gastric dendritic cells (DCs). This interaction perimeter and the surface area of the apical membrane induces inhibition of Th1 cell differentiation as had become substantially reduced. As a result and compared to nonbinding variants. Le+ antigen alter the consistent with their hypothesis, CagA expressing cells host’s T cell ability to differentiate by reducing the acquired an elongated, spindle-shaped morphology, amount of IL-6 produced and blocks Th 1 cell and lost their connections with the apical junctions of polarization. Similar to the Treg suppression of the immune response, the binding of Le+ antigen to DC- SIGN reduces IL-6 levels which may lead to increased Hey SHP-2 Wanna Bind Tonight?
T cell sensitivity to suppression. Therefore, H. pylori targets DC-SIGN to block a polarized Th1 cell response A study conducted by Shiho Yamazaki et al. (2003) by phase-variable expression of Le antigens. Once suggests that the CagA protein then may bind, undergo again, decreased proliferation of Th1 cells lead to a tyrosine phosphorylation, and form an activated- decrease in the host’s immune response (14). complex with SRC homology 2 Domain (SHP-2). The phosphorylation of CagA and activation of SHP-2 are thought to induce the hummingbird phenotype: a Response:
Inflammation
CagA Disrupts IL-1β
Vaccines?
Figure 2. Pathogen-Host Interactions in the Pathogenesis of H. pylori Infection
Bacterial virulence factors CagA and VacA cause damage to the host cell. In response to bacterial colonization, a host mounts an immune
response which often leads to disease. Several host proteins: ZO-1, SHP-2, c-Met, IL-1b, and Erk have been noted to be affected by CagA
leading to formation of duodenal and gastric ulcers as well as gastric cancer. However, there are other effects of CagA that remain
unknown and must be addressed in future research. Several treatments are used as a means to eradicate H. pylori infection such as
antibiotics. Recent research proposes several alternative methods of treatment such as: mastic gum, genome-based drugs, and vaccines.
Further research is still needed to clearly understand the pathology caused by H. pylori and optimal treatments.
morphological change characterized by elongation and cells. In a study conducted by Yuri Churin et al. (2003), contraction of the cell and increased cell motility. the interaction of CagA with this receptor was tested. Normal SHP-2 is actively involved in regulation adhesion, spreading, and migration of cells. The Small interference RNA was used to block the scientists took biopsies at eight different parts of the expression of c-met. The blocking of c-Met expression stomach lining from fifteen patients who had either inhibited scattering in AGS cells infected with CagA (+) gastritis or early gastric cancer. The biopsies were submitted to immunoblotting and immunoprecipitation in What’s a Gut to do?
phosphotyrosine, and SHP-2. The results detected the presence of tyrosine phosphorylated CagA protein and Current treatment of Helicobacter pylori infection, which CagA-coimmunoprecipitated endogenous SHP-2. This ultimately leads to the development of peptic ulcers, is suggests that deregulation of SHP-2 by translocated based on multiple drug therapies (22). Currently, the CagA can cause abnormal morphology and movement most effective therapy consists of a proton-pump inhibitor and a series of three antibiotics chosen from Please Don’t Phosphorylate When Erk is Home
including two drugs (proton pump inhibitor and an Hideaki Higashi et. al (2004) investigated cellular antibiotic) and four drugs (proton pump inhibitor, three proteins that bind to phosphorylated tyrosine but not antibiotics), have also proven to eradicate H. pylori non-phosphorylated CagA and form complexes SHP-2 and subsequently with extracellular signal-regulated kinase (Erk), a MAP kinase signaling molecule that is The Basic PPIs
thought to effect cell proliferation and motility. To test the effect on the humming bird phenotype, they created Proton pump inhibitors (PPIs) play an essential role in a knock-out SHP-2 and transfected it into AGS cells. the eradication of H. pylori. PPIs act within the parietal They found that only phosphorylated CagA complex cells of the stomach to inhibit H+, K+-ATPase activity. with SHP-2 binds to and abnormally prolongs the This enzyme maintains the balance of H+ and K+ ions within the cell so that pH is maintained inside and outside of the cell. PPIs bind to the H+, K+-ATPase on CagA Sticks like C-Met
the outer luminal membrane and inhibit phosphorylation of ATP molecules. This in turn prevents the exchange C-Met is a hepatocyte growth factor/scatter factor of H+ and K+ ions. With the enzyme blocked, the acidic receptor that is involved in invasive growth of tumor pH of the stomach is made more basic so that antibiotics, which are taken along with PPIs, may reach Just Say No to Drugs
the H. pylori living within the epithelial cells of the The reason that there are so many choices in antibiotic combinations when considering treatment of H. pylori is All PPIs are NOT Created Equal
antibiotic resistance. A patient’s level of resistance to an antibiotic can cause a drug regimen to fail in There are several PPIs that may be used in erradicating infection. Ecclissato et. al. (2002) studied combination with antibiotics to eradicate H. pylori. The the effects of antibiotic resistance in two common regimens used to treat infection by H. pylori. In both a Pantoprazole, Lansoprazole, and Rabeprazole. PPI three drug regimen and a two drug regimen, it was differences depend on the H+, K+-ATPase binding shown that when a patient was resistant to just one location and their pharmacokinetic properties. antibiotic, the overall eradication rate of the regimen In comparison, Hellstrom and Sigurd (2004) found that was decreased by half (28). This has serious Rabeprazole was very quick to inhibit acid production implications for the treatment of patients for H. pylori compared to the others; however, Omeprazole offered the most potent acid inhibition. Pantoprazole and Currently, doctors do not test patients for Lansoprazole are not far behind Omeprazole and antibacterial resistance before they are prescribed a Rabeprazole in speed and potency, indicating that all regimen to treat H. pylori infection (28). If these patients four of these PPIs are effective ways to inhibit the are resistant to the bacteria, the regimen is likely to fail. function of the H+, K+-ATPase enzyme (23). In countries such as the United States, where drugs are readily available ,regimen failure is not as serious as in Dealing the Drugs
countries where drugs are not easily obtained (28). Bacteria form resistance to antibiotics in ways Current therapies used to eradicate H. pylori in the unique to each antibiotic. H. pylori resistance to ß- stomach all include at least one antibiotic in Lactam antibiotics is due to alteration in the Penicillin combination with a PPI. The main categories of Binding Protein (PBP) (26). Studies have shown that antibiotics used are: macrolide antibiotics, ß-Lactam the replacement of the the wild-type HP0597 (PBP1A) antibiotics, and Metronidazole antibiotics (21). gene by the Hardenberg PBP1A resulted in a huge increase in the minumum inhibitory concentration (MIC) Holy Macrolide
of amoxicillin (a ß-Lactam antibiotic) (26). Antibacterial resistance is usually due to the bacteria evolving ways Macrolide antibiotics accumulate in the epithelial to produce ß-Lactamase even in the presence of anti β- tissues of the stomach. Here, they are able to inhibit lactam antibiotics. Structural alterations in a PBP or RNA- dependent protein synthesis by binding to the changes in other proteins that are involved in cell wall 23S ribosomal RNA in the 50S subunit of prokaryotic synthesis are also involved in antibacterial resistance. ribosomes.When the macrolides bind to the ribosomes, Macrolide antibiotics face two main modes of they inhibit peptidyl transferase reactions and cause resistance. There is target site modification, during incomplete peptide chains to be detatched from the which the bacterium makes an enzyme that methylates ribosome. Proteins are essential for a cell to funciton, the rRNA, thus inhibiting the binding of erythromycin (or so without properly formed proteins, the bacteria die other macrolides) (24). The second mode of resistance is alteration in transport of the antibiotic. This mode of resistance involves two macrolide efflux pumps: A and And The Walls Came Tumbling Down
E. The pumps pump macrolides out of the cell; however, this mode of resistance only works on ß-Lactam antibiotics are analogues of D-alanyl-D- fourteen or fifteen membered macrolides (24). alanine, which is an amino acid that makes up Metronidazole resistance has been accredited to peptidoglycan. This close relationship allows ß-Lactam mutations in the rdxA gene that make the gene antibiotics to bind to the active site of penicillin binding inoperative (29). This gene coded for an oxygen- protiens (PBPs) within bacteria. PBPs facilitate the insensitive NADPH nitroreductase (29). Without the transpeptidation of the cell walls of bacteria. When ß- expression of this gene, the Metronidazole cannot Lactam antibiotics bind to the active site of PBPs and inhibit transpeptidation of peptidoglycan, they prevent cell wall synthesis within the bacteria (25). Without cell Glimpses of Future Glory
walls, parent cells are not able to undergo mitosis to generate a new generation of bacterial cells. Therefore, Currently, Genome-based drugs and vaccines are being worked on. Genome-based drugs are drugs that attack a specific target, which is essential to cell Where’s the Air
function (21). Researchers are trying to find proteins involved in cell envelope synthesis and integrity, cell Metronidazole antibiotics only work on anaerobic division, protein synthesis, nucleic acid biosynthesis, bacteria like H. pylori (27). When a metronadizole gene expression and regulation, cell metabolism and antibiotic enocunters an anaerobic bacterium, the nitro other protein essential to H. pylori function that may be group of the metronidazole is reduced, thus interfering with DNA synthesis and making it possible for the antibiotic to interact with intracellular macromolecules An important topic of research that many scientists are very interested in is the possibility of a vaccination for Conclusion
H. pylori infection. It is believed that a vaccination is possible due to the immune response generated by the Since its discovery in 1983, research has shown host at the onset of H. pylori infection (29). It has been Helicobacter pylori to be the cause of peptic ulcers and found that H. pylori actually benefit from this response a contributor to gastric cancer. Further studies on the when first colonizing a new host. The antigens formed bacterium have given scientists insight into how the in this process may be used to treat established bacterium functions in the human body and how it may be eradicated. Advances in the knowledge of H. pylori Most research concerning vaccines has been will help scientists and physicians effectively treat carried out in animal models with promising results. It gastric and duodenal ulcers as well as gastric cancer. was found by Ghiara et. al. (1997) that mice that had chronic H. pylori infection were able to receive Acknowledgements
therapeutic vaccinations of recombinant VacA and CagA together with a genetically detoxified mutant of We would also like to thank Michael Zorniak, Jenny the heat-liable enterotoxin LTK63, intragastrically, to Riddle, Katie Hampton and Michael Wollar for their eradicate H. pylori infection (31). Furthermore, the guidance and expertise. We would like to thank Dr. vaccination protected the mice from re-infection for 12 DebBurman for his time and patience. Using animal models, scientists are currently Note: Eukaryon is published by students at Lake Forest testing different possible vaccines for efficacy and College, who are solely responsible for its content. The safety, as well as considering the best mode of delivery views expressed in Eukaryon do not necessarily reflect (32). A big challenge for scientists to overcome in those of the College. Articles published within Eukaryon eradicating H .pylori is antibiotic resistance. should not be cited in bibliographies. Material contained herein should be treated as personal communication and should be cited as such only with the consent of In order to lessen the possibility of antibacterial resistance and subsequent ineffectiveness of drugs in treating H. pylori, alternative treatments should be References
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