By M. Lisk. Austin Peay State University. 2018.

Prokaryotic and Eukaryotic Microorganisms According to a proposal by Woese that has been gaining general acceptance in recent years rumalaya liniment 60 ml overnight delivery muscle relaxant iv, the world of living things is classified in the three domains bac- teria generic 60 ml rumalaya liniment mastercard muscle relaxant agents, archaea, and eucarya. In this system, each domain is subdivided into Kayser, Medical Microbiology © 2005 Thieme All rights reserved. This domain includes the kingdom of the heterotrophic eubacteria and includes all human pathogen bacteria. The other kingdoms, for instance that of the photosynthetic cyanobacteria, are notpathogenic. It is estimated that bacterial spe- cies on Earth number in the hundreds of thousands, of which only about 5500 have been discovered and described in detail. This domain includes forms that live under extreme environmental con- ditions, including thermophilic, hyperthermophilic, halophilic, and methanogenic microorganisms. The earlier term for the archaea was archaebacteria (ancient bac- teria), and they are indeed a kind of living fossil. Thermophilic archaea thrive mainly in warm, moist biotopes such as the hot springs at the top of geothermal vents. The hyperthermophilic archaea, a more recent discovery, live near deep-sea volcanic plumes at temperatures exceeding 1008C. The plant and animal kingdoms (animales and plantales) are all eukaryotic life forms. These organisms are obligate intracellular parasites that are able to reproduce in certain human cells only and are found in two stages: the infectious, nonreproductive particles called elementary bodies (0. These organisms are obligate intracellular parasites, rod- shaped to coccoid, that reproduce by binary transverse fission. Theyare found in a wide variety of forms, the most common being the coccoid cell (0. Fungi (Mycophyta) are nonmotile eukaryotes with rigid cell walls and a classic cell nucleus. They contain no photosynthetic pigments and are carbon heterotrophic, that is, they utilize various organic nutrient substrates (in contrast to carbon autotrophic plants). Of more than 50 000 fungal spe- cies, only about 300 are known to be human pathogens. Protozoa are microorganisms in various sizes and forms that may be free-living or parasitic. They possess a nucleus containing chromo- somes and organelles such as mitochondria (lacking in some cases), an en- Kayser, Medical Microbiology © 2005 Thieme All rights reserved. Host–Pathogen Interactions 7 doplasmic reticulum, pseudopods, flagella, cilia, kinetoplasts, etc. Many para- sitic protozoa are transmitted by arthropods, whereby multiplication and 1 transformation into the infectious stage take place in the vector. Medically signif- icant groups include the trematodes (flukes or flatworms), cestodes (tape- worms), and nematodes (roundworms). These animals are characterized by an external chitin skele- ton, segmented bodies, jointed legs, special mouthparts, and other specific features. Their role as direct causative agents of diseases is a minor one (mites, for instance, cause scabies) as compared to their role as vectors trans- mitting viruses, bacteria, protozoa, and helminths. Host–Pathogen Interactions & The factors determining the genesis, clinical picture and outcome of an infection include complex relationships between the host and invading or- ganisms that differ widely depending on the pathogen involved.

Important terminology used when discussing transcription is illustrated in Figure 1-3-2 cheap 60 ml rumalaya liniment amex spasms below left rib cage. In the vicinity of a gene purchase rumalaya liniment 60 ml without a prescription spasms of the heart, a numbering system is used to identify the location of impor- tant bases. Transcription of the following sequence of the tryptophan operon occurs in the direction indicated by the arrow. Find the option with a sequence identical to the coding strand (remember to substi- tute U for T, if necessary). Alternatively, if you prefer to find the complement of the template strand, you will get the same answer. Termination of transcrip- tion sometimes requires a protein called rho (p) factor. The requirements for termination of transcription in eukaryotes are not well understood. The promoter identifies the start site for tran- scription and orients the enzyme on the template strand. The structure and transcription of a typical eukaryotic gene coding for a protein is illustrated in Figure 1-3-6. The poly-A tail protects the message against rapid degradation and aids in its transport to the cytoplasm. Variants of the muscle proteins tropomyosin and troponin T are produced in this way. The synthesis of membrane-bound immunoglobulins by unstimulated B lymphocytes, as opposed to secreted immunoglobulins by antigen-stimulated B lymphocytes, also involves alternative splicing. The primary transcripts from a large percentage of genes undergo alternative splicing. Alternative splicing can be detected by Northern blot, a technique discussed in Chapter 7. The Composition of Prokaryotic and Eukaryotic Ribosomes The large and small prokaryotic ribosomal subunits are 505 and 305, respectively. They are a function of both size and shape, and therefore the numbers are not additive. Many proteins undergo posttranslational modifications as they prepare to assume their ultimate roles in the cell. Important features of the genetic code include: • Each codon consists of three bases (triplet). Protein syn- thesis begins with methionine (Met) in eukaryotes, and formylmethionine (fmet) in prokaryotes. For those amino acids having more than one codon, the first two bases in the codon are usually the same. They can also cause changes in enzyme activity, nutritional requirements, antibiotic susceptibility, morphology, antigenicity, and many other properties of cells. Effects of Some Common Types of Mutations on Protein Structure Type of Mutation Effect on Protein I I i Silent: new codon specifies same amino acid None I Ii! Missense: new codon specifies Possible decrease in function; variable effects I I different amino acid I l Shorter than normal; usually nonfunctional Nonsense: new codon is stop codon i Frameshift: deletion or addition of a base Usually nonfunctional; often shorter than normal!

The primary transcripts from a large percentage of genes undergo alternative splicing discount rumalaya liniment 60 ml without prescription muscle relaxant walmart. Alternative splicing can be detected by Northern blot buy rumalaya liniment 60 ml amex spasms when falling asleep, a technique discussed in Chapter 7. The Composition of Prokaryotic and Eukaryotic Ribosomes The large and small prokaryotic ribosomal subunits are 505 and 305, respectively. They are a function of both size and shape, and therefore the numbers are not additive. Many proteins undergo posttranslational modifications as they prepare to assume their ultimate roles in the cell. Important features of the genetic code include: • Each codon consists of three bases (triplet). Protein syn- thesis begins with methionine (Met) in eukaryotes, and formylmethionine (fmet) in prokaryotes. For those amino acids having more than one codon, the first two bases in the codon are usually the same. They can also cause changes in enzyme activity, nutritional requirements, antibiotic susceptibility, morphology, antigenicity, and many other properties of cells. Effects of Some Common Types of Mutations on Protein Structure Type of Mutation Effect on Protein I I i Silent: new codon specifies same amino acid None I Ii! Missense: new codon specifies Possible decrease in function; variable effects I I different amino acid I l Shorter than normal; usually nonfunctional Nonsense: new codon is stop codon i Frameshift: deletion or addition of a base Usually nonfunctional; often shorter than normal! Triplet repeat expansion Expansions in coding regions cause protein product to be longer than normal and unstable. Crossover or recombination between homologous chromosomes is a normal part of meiosis I that generates genetic diversity in reproductive cells (egg and sperm), a largely beneficial result. In a normal crossover event, the homologous maternal and paternal chromo- somes exchange equivalent segments, and although the resultant chromosomes are mosaics of maternal and paternal alleles, no genetic information has been lost from either one. On rare occasions, a crossover can be unequal and one of the two homologs loses some of its genetic information. Maternal Paternal Normal Crossover Deletion from Paternal Chromosome ~ Figure 1-4-3. As illustrated in Figure 1-4-4, if a splice site is lost through mutation, spliceosomes may: Delete nucleotides from the adjacent exon. Mutations in splice sites have now been documented in many different diseases, including ~-thalassemia, Gaucher disease,. Adds Nucleotides From Intron i i Removes Exon Nucleotides i i Exon Skipping i i Figure 1-4-4. Inaccurate Splicing After Mutation in a Splice Site I ~-Th~lassemia - l i There are two genes for the beta chain of hemoglobin. In ~-thalassemia, there is a deficiency I I of ~-globin protein compared with a-globin. A large number of ~-globin mutations have I I been described, including gene deletions, mutations that slow the transcriptional process, I I and translational defects involving nonsense and frameshift mutations. A 9-month-old infant of Greek descent was brought to the hospital by his parents because he became pale, listless, and frequently irritable. The attending physician noted that the spleen was enlarged and that the infant was severely anemic. It is believed that, similar to, sickle cell anemia and glucose-6-phosphate dehydrogenase deficiency, the abnormality of! Splenomegaly is due to the role of the spleen in clearing damaged red cells from the bloodstream.

For example purchase rumalaya liniment 60 ml free shipping spasms hip, knowing that a specific compound class interacts strongly with a particular peptide motif at various receptors/catalytic sites will facilitate the identification of lead compounds for receptors/enzymes with similar motifs purchase rumalaya liniment 60 ml on-line spasms right side. Generic approaches towards the identification of new targets for human drug discovery are now routinely practised within pharmaceutical companies. Simply trawling these databases for potential targets expressed in diseased tissue has already yielded novel homologs of key enzymes and receptors, many of which have been patented as drug discovery targets. We are still at an early stage of understanding the full complexity of the mammalian and human genetic vocabulary. A more pharmaceutically oriented approach is to search for novel members of certain key receptor families which are already known from pharmacological studies to be present in a target tissue. This combination of pharmacology and molecular biology is proving particularly interesting, identifying far greater heterogeneity amongst targets than had previously been thought, with both receptor subtypes and the differential splicing of individual genes contributing to this complexity. The effective management of chemical and biological data underpins the effectiveness of any drug discovery group. All these aspects of drug discovery will impinge on drug delivery and targeting in the future. Furthermore, combinatorial chemistry and high-throughput screening will provide targeting molecules for disease-associated surface-expressed receptors and ligands. These may be linked to therapeutic drug molecules to increase epithelial transport by active transport processes and drug targeting selectivity. Describe the potential roles of proteomics and genomics in drug delivery and targeting. Identify two ways in which combinatorial chemistry may impinge on drug delivery and targeting. The preceding chapters in the last part of this book have highlighted the recent developments in gene therapy, drug discovery, genomics and proteomics as a consequence of the recent developments in molecular biology and chemistry. This chapter concludes this text by examining how the advances in chemistry and biology are providing opportunities for more effective site-specific drug targeting and bioresponsive pulsatile drug delivery. The chapter considers the development of prodrug-based technologies for cell-specific drug delivery, provides an overview of the use of smart polymeric systems, microchips and genetically engineered cell-based implants in addressing the challenges of chronopharmacology, and offers a perspective of the future of drug delivery and targeting in this new millennium. In the discovery process opportunities exist, as illustrated in Chapter 15, to identify cell-specific enzymes and ligands which may be used to target drugs to these cells. The integration of the considerations for drug delivery and targeting into the drug design process may ultimately allow the development of drugs which are not just potent and non-toxic but offer the advantage that their chemical structure dictates the targeting of the drug to its particular site of action through enzyme-based chemical delivery systems using prodrugs. A prodrug is a pharmacacologically inactive compound which undergoes chemical or enzymatic metabolism to the active. Some of the early pharmaceuticals were found to be prodrugs and this finding has led to the subsequent introduction of the metabolite itself into therapy, particularly in cases where the active metabolite is less toxic or has fewer side-effects than the parent prodrug. The administration of the active metabolite may also reduce variability in clinical response between individuals due to differences in pharmacogenetics. Most chemically designed prodrugs consist of two components; the active drug chemically linked to a pharmacologically inert moiety. The prodrug must be sufficiently stable to withstand the pharmaceutical formulation while permitting chemical or enzymatic cleavage at the appropriate time or site. After administration or absorption of the prodrug, the active drug is usually released by either chemical or enzymatic, hydrolytic or reductive processes. Prodrugs are most commonly used to overcome the biological and pharmaceutical barriers which separate the site of administration of the drug from the site of action (Figure 16. Prodrug design has been used to address a wide range of pharmaceutical problems including: • unpalatability • gastric irritation • pain on injection • insolubility • instability. Prodrug design has also been used widely to address pharmacological problems such as poor drug adsorption and drug distribution.