Sequencing of Bacterial Genomes: Principles and Insights into Pathogenesis and Development of Antibiotics
Abstract
:1. Introduction
2. Brief Overview of Bacterial Pathogenesis
- Adherence factors: these are attachment devices such as pili, fimbriae, and adhesins which enable pathogenic bacteria to adhere to host cells. For example Escherichia coli, a common aetiological agent of urinary tract infection, attaches to uroepithelial cells by means of pyelonephritis-associated pili [1,6,7]. In the pathogenesis of gonorrhea, Neisseria gonorrhoeae attaches to mucosa epithelial cells by means of type IV pili and an outer membrane adhesion, Opa [1,6,8].
- Toxin production: Various exotoxins are elaborated by pathogenic bacteria, which include cytotoxin, enterotoxin and neurotoxin [9]. Corynebacterium diptheriae, the aetiological agent of diphtheria produces a heat labile cytotoxin. In the presence of NAD, Fragment A component of the toxin inactivates EF-2, causing the inhibition of polypeptide elongation and therefore protein synthesis [10]. Vibrio cholerae, the cause of cholera produces an enterotoxin which activates the adenylate cyclase enzyme in intestinal mucosa cells resulting in high levels of intracellular cAMP, and also the secretion of water and ions into the small intestine lumen [1,11,12]. Tetanus is mediated by a neurotoxin produced by Clostridium tetani; the toxin prevents the release of γ-aminobutyric acid thereby causing spastic paralysis [13]. In addition to exotoxins, endotoxin may be produced by Gram-negative bacteria, especially when they lyse. Endotoxins are essentially lipopolysaccharides which can induce overwhelming inflammatory responses and are important in sepsis and septic shock [7,9].
- Invasins: these include a wide range of extracellular enzymes or proteins which enable bacterial pathogens to invade host tissues. Using Staphylococcus aureus as an example, this organism produces a wide range of invasins including hyaluronidase which breaks down hyalauronic acid of connective tissues, DNases which break down DNA, haemolysins which split red blood cells, staphylokinase which activates plasminogen to plasmin, an enzyme digesting fibrin clots [1,14,15]. Several other invasins such as proteases, lipases, nucleases, collagenase and elastase are produced by Staphylococcus aureus [1,14].
- Capsule: bacterial capsule contributes to the virulence of some bacteria such as Streptococcus pneumoniae and Neisseria meningitidis by helping them resist phagocytosis of the host defense system [1].
3. Brief Overview of the Interactions between Bacteria and Antibiotics
- Inhibition of cell wall synthesis: The most important drugs in this group are the β-lactams that bind and inhibit penicillin binding proteins which catalyze formation of peptidoglycan cross-links in the bacterial cell wall [23,25,26,27]. This action weakens the cell wall of the bacterium causing cytolysis [27].
- Inhibition of protein synthesis: drugs of this class include aminoglycosides, tetracyclines, macrolides, and chloramphenicol; they act at the level of the ribosome and interfere with protein synthesis at various stages [23]. Tetracycline blocks attachment of the transfer RNA-amino acid to the ribosome, thereby inhibiting codon-anticodon interaction [28]. Erythromycin binds to the 23S rRNA molecule (in the 50S subunit) of the bacterial ribosome and blocks exit of the growing peptide chain [23,26]. Chlorampheicol binds to the 23S rRNA of the 50S bacteria ribosomal subunit and inhibits the peptidyl transferase activity and therefore elongation of the protein chain [23,25].
- Inhibition of nucleic acid synthesis: common drugs in this group include fluoroquinolones and rifamycins. Fluoroquinolones act by inhibiting DNA gyrase, an enzyme which introduces negative supercoils in the bacterial DNA prior to initiation of DNA replication [23,25,26]. Fluoroquinolones also inhibit Topoisomerase IV, which is responsible for removing the separating daughter chromosomes at the end of a round of replication [23,25,26]. Rifampin inhibit bacterial RNA polymerase, which occurs as a result of the antibiotic binding in the polymerase subunit deep within the DNA/RNA channel, causing direct blocking of the growing or elongating RNA [25,26].
- Inhibition of metabolic pathways: notable drugs in this group are sulfonamides and trimethoprim. Sulfonamides are chemical analogs of para-aminobenzoic acid and competitively inhibit dihydropteroate synthetase [23,25]. Trimethoprim inhibits dihydrofolate reductase, an enzyme that reduces dihydrofolic acid to tetrahydrofolic acid [25,26]. Both dihydropteroate synthetase and dihydrofolate reductase are important in the production of bacteria folic acid which is required for nucleotides, necessary for DNA synthesis [29].
- Mutational alteration of the target protein
- Enzymatic inactivation of the drug
- Preventing drug access to targets
- Permeability barriers
- Acquisition of genes for less susceptible target proteins from other species
- By passing of the target
4. Antibiotic Discovery in the Pre-genome Era
5. Bacterial Genomes and Genome Sequencing
5.1. Bacterial Genomes
5.2. Principles of Genome Sequencing
Method | Single-Molecule Real-Time Sequencing (Pacific Bio) | Ion Semiconductor (Ion Torrent Sequencing) | Sequencing by Synthesis (Illumina) | Chain Termination (Sanger Sequencing) |
---|---|---|---|---|
Read length | 2,900 bp | 200 bp | 50 to 250 bp | 400 to 900 bp |
Accuracy | 99% | 98% | 98% | 99.9% |
Reads per run | 35–75 thousand | up to 5 million | up to 3 billion | N/A |
Time per run | 30 min to 2 h | 2 h | 1 to 10 days, | 20 min to 3 h |
Cost per 1 million bases (in US$) | $2 | $1 | $0.05 to $0.15 | $2,400 |
Advantages | Rapid and has longest read length. | Equipment is relatively less expensive and Fast. | Sequence yield could be very high depending upon equipment model | Long individual reads. Wide application |
Disadvantages | Yield tends to be low at high accuracy. Equipment is very expensive. | Prone to homopolymer errors. | Equipment can be very expensive. | Equipment is expensive and not suitable for larger sequencing projects. |
References | [46,48]. | [46,47] | [43,44,46] | [39] |
5.3. Streptococcus Pneumoniae TIGR4 Genome: An Example of a Sequenced Genome
5.4. Genome Sequencing and Insights into Bacterial Pathogenesis
5.5. Genome Sequencing and Insights into Development of Antibiotics
6. Conclusions
Conflicts of Interest
References
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Donkor, E.S. Sequencing of Bacterial Genomes: Principles and Insights into Pathogenesis and Development of Antibiotics. Genes 2013, 4, 556-572. https://doi.org/10.3390/genes4040556
Donkor ES. Sequencing of Bacterial Genomes: Principles and Insights into Pathogenesis and Development of Antibiotics. Genes. 2013; 4(4):556-572. https://doi.org/10.3390/genes4040556
Chicago/Turabian StyleDonkor, Eric S. 2013. "Sequencing of Bacterial Genomes: Principles and Insights into Pathogenesis and Development of Antibiotics" Genes 4, no. 4: 556-572. https://doi.org/10.3390/genes4040556