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Antibiotic resistant bacteria Karl Ochs Introduction History of Antibiotics Antibiotics have been in use for many years in treatment of infections. It was until the last century that people knew the infections that are caused by bacteria. The ancient Egyptians used various plant extracts and moulds to treat infections. In the 20th century, it was realized that some infections such as diarrhea and pneumonia were caused by bacteria and they were the leading cause of death in developed countries (1). Paul Ehrlich, a German physician in the 19th century some bacterial cells were colored unlike others. This made him come to a conclusion that some bacterial cells could be killed selectively without other cells being harmed. Arsphenamine was found in 1909 to be effective in treatment of Syphilis. This was referred to be the first modern antibiotic even though it was called chemotherapy during that time.30 years, Selman Waksman discovered more than 20 antibiotics. In 1928, Alexander Fleming discovered penicillin accidentally as Penicillium notatum had created bacteria free zones on a plate. It was isolated and grown in pure culture. Mass production of penicillin was done. There was a huge fire in Boston in the United States and many people died due to infection by Staphylococcus. Penicillin was used successfully in the treatment of this. In 1945, Alexander Fleming, Howard Florey and Ernest Chain were awarded for mass production of antibiotics. Introduction to resistance This is the ability of a bacteria to resist medication previously used against them. Resistance occurs due to one of three reasons that is random mutations, misuse of antimicrobial agents and genetic mutations. Those microbes that are resistant to many antimicrobials are referred to as multidrug resistant. Many infections are not treatable today because of resistance. Resistance can be attributed to high use of antibacterial in the human population and animals and an increased resistant strains in both human and nonhuman sources (2). Thesis statement Infectious diseases have challenged humanity since time immemorial. We have however developed antibiotics to do away with the infections that have challenged us since our existence. Since the introduction of Penicillin as the first antibiotic, other antibiotics have been developed to counter even bacterial infections. Despite this achievement, as humans have evolved in their ways of fighting bacteria, the bacteria itself has been evolving during this period. There is a growing number of resistant bacteria today. In this paper, I will examine the difference between gram positive and gram negative bacteria, the mechanisms of action of some bacteria and the types of resistant bacteria in place today. Types of bacteria Eukaryotes vs Prokaryotes Cell walls Antibiotic resistant bacteria Karl Ochs Page 2 of 12 The cell wall of prokaryotic cells if present contains peptidoglycan or mucopeptide while in eukaryotic cell, if the cell wall is present then it contains cellulose and peptidoglycan is absent Peptidoglycan This is part of prokaryotic cell wall that forms a mesh like layer outside the plasma membrane. It has alternating residues of N-acetylmuramic acid and N acetylglucosamine. A peptide chain of there to five amino acids is attached to N-acetylglucosamine. (Source: 4) A peptidoglycan layer is formed by two alternating amino sugars NAM and NAG which are joined by a glycosidic bond. Both of the amino sugars have L-alanine, mesodiaminopimelic acid, D-glutamine and L-lysine but in different compositions. The cross linking of these amino acids is carried out by the enzyme DD transpeptidases (3). Antibiotic resistant bacteria Karl Ochs Page 3 of 12 Gram positive vs gram negative prokaryotes What’s the difference, thickness and surroundings. Gram positive prokaryotes do not have an outer membrane. Their cell wall is 2030nm thick and they contain 70-80% murein. The cell wall is smooth and has teichoic acids. The lipid content is very low and the cell wall does not have porins. In gram negative prokaryotes, the outer membrane is present. The cell wall is wavy and comes into contact with the plasma membrane in a few loci. The cell wall is 8-12nm thick. Lipid content in the cell wall is about 20-30%.In the outer membrane, hydrophilic channels or porins occur. Teichoic acids are however absent unlike in gram positive prokaryotes Other minor differences between the two include that the basal body of the flagellum in gram positive prokaryotes cell wall contain two rings and that mesosomes are quite prominent. In gram negative prokaryotes, the basal body of the flagellum has four rings and mesosomes are not as prominent as in gram positive prokaryotes (Source: 4). Antibiotic resistant bacteria Karl Ochs Page 4 of 12 How to test, how it works Differences between gram positive and gram negative prokaryotes can be tested by use of gram staining. The test is based on differences in cell wall constituents between the two groups of prokaryotes. The gram stain procedure distinguishes between gram positive and negative by formation of either red or violet color. The thick layer of peptidoglycan in gram positive bacteria make them to stain violet. In gram negative prokaryotes, the peptidoglycan wall is thinner and they therefore stain red (5). Gram staining involves three main processes. In the first stage, staining with a water soluble dye known as crystal violet is done followed by crystal violet and then counterstaining. Cells are stained with crystal violet and iodine solution is added leading to a complex formation which is insoluble in water. A decolorizer such as acetone is added to dehydrate the peptidoglycan layer. The crystal violet and iodine complex are not able to pass through the peptidoglycan layer. In gram negative prokaryotes, the outer membrane is degraded and the peptidoglycan will retain the crystal violet-iodine complex. During the counterstain step, a water soluble safrarin is added to the sample to be tested and it stains it red. Safrarin is lighter than crystal violet but is does not however affect the purple coloration in gram positive bacteria cells. In gram negative bacteria, the cells are stained red. Antibiotic resistant bacteria Karl Ochs Page 5 of 12 How antibiotics work What antibiotics do There are similarities and differences between the human and bacteria cells. Antibiotics work by disrupting processes in bacterial cells only. Since human cells do not have cell walls unlike bacteria, antibiotics like penicillin will work by keeping the bacteria from building a cell well. The formation of peptidoglycan layer, a component of cell wall is inhibited. Human cells and bacteria also differ in their cell membranes and machinery they use in the replication of DNA. It has been found that some antibiotics dissolve bacterial cells membrane while others affect DNA copying machinery or protein building which is specific to bacterial cells. Different classes Beta-Lactams. Penicillins and Cephalosporins. Their mode of action is mainly inhibition of cell wall synthesis. They are characterized by a four membered beta lactam that is at the center of the structure. This class of antibiotics also target penicillin binding proteins which are groups of enzymes found in the cell membrane. The enzymes are involved in formation of cross links with the bacterial cell wall. The Penicillin binding proteins have been found to be bound to the betalactam ring and therefore they do not perform their functions in cell wall synthesis. Eventually, this lead to bacterial cell death because of autolysis or osmotic instability Antibiotic resistant bacteria Karl Ochs Page 6 of 12 Macrolides. They are also referred to as protein synthesis inhibitors. The main mechanism of action is inhibition of protein biosynthesis in bacteria. This inhibition has been known to be caused by prevention of peptidyltransferase from adding a peptide group attached to a transferRNA in the adjacent amino acid. It has been also suggested that another mechanism of action of this class of antibiotics is that they cause premature dissociation of peptidyl transfer RNA from the ribosome. Their action is considered to be bacteriostatic as they reversibly bind to the P site of the 50S subunit of the bacterial ribosome. Fluoroquinolones. Together with quinolones, this class of drugs inhibit bacterial replication by affecting the DNA replication pathway of bacterial cells. DNA houses the genetic materials of bacterial cells and it is indeed necessary for the normal functioning of a cell. Double stranded DNA unwinds during the process of replication and this allows complementary base pairing to take place. DNA unwinding is done by enzymes DNA Topoisomerase and DNA gyrase. DNA gyrase is a Topoisomerase II enzyme that leads to unwinding of DNA by causing negative supercoils and also cause relaxation of positive supercoils. Fluoroquinolones therefore inhibit this enzyme through binding to A-subunit. This means that bacterial cells would not be able to replicate and carry out protein synthesis. Tetracyclines. The main mechanism of action of Tetracyclines is that they inhibit proteins synthesis in bacterial cells by preventing the attachment aminoacyl transfer RNA to an area Antibiotic resistant bacteria Karl Ochs Page 7 of 12 of the ribosome called A site. Binding occurs in the 30S subunit of bacterial ribosomes. Through this process, introduction of amino acids to the nascent peptide chain are prevented. Upon withdrawal of the drug, this action can however be reversible (Anon). Aminoglycosides. This class of drugs exhibit a concentration dependent activity against gram negative bacteria. Their mechanism of action is also inhibition of protein synthesis. They disturb peptide elongation at the 30S ribosomal subunit of bacterial cells. This gives rise to inaccurate translation of messenger RNA therefore the biosynthesis of proteins in bacterial cells is stopped. Subsets of aberrant proteins that were incorporated into the cell membrane of bacteria could affect its permeability (6). How resistance is gained in bacteria Evolution theory Basic evolution theories With the introduction of new antibiotics, development of resistance has been inevitable. Antibiotic resistance in any given bacteria may be related to the traits of the organism for example cell wall characteristics that make it to be naturally resistant .In acquired resistance, it results from mutations in its DNA and resistance conferring DNA from another organism may be acquired. According to the gene transfer theory, spontaneous antibiotic resistance frequency increases. Although the process of mutation is very rare, it doesn’t take a long time before resistance to a particular resistance is developed in a population. In vertical evolution, Antibiotic resistant bacteria Karl Ochs Page 8 of 12 resistance genes are transferred to the bacteria`s progeny directly during the process of DNA replication According to the horizontal gene transfer theory, genetic material are housed in small section of DNA that can be passed between the individual bacteria with the same or different species. Transduction, transformation or conjugation processes are associated with horizontal gene transfer. Examples of bacteria gaining resistance Penicillin, penicillinase example Resistance has developed for some antibiotics that were used in treatment of bacterial infections in the past. Examples of this include Neisseria gonorrhoeae and Staphylococcus aureus which have now become resistant to benzyl penicillin. However, the infections caused by these bacteria in the past have been treated by this antibiotic (7). Some bacteria have become resistant to even the most accessible antibiotics. This is a major public health problem since these bacteria are in a position to cause life threatening infections. They include Staphylococcus aureus which is resistant to methicillin antibiotic while Enterococcus is resistant to Vancomycin. Mycobacterium tuberculosis bacteria is resistant to many antibiotics including penicillin. The growing concern of antibiotic resistant bacteria According to the World Health Organization, antibiotic resistance has been a global public health threat that requires immediate action across all governments. Klebsiella pneumonia bacteria has developed resistance for many drugs. Carbapenems have been Antibiotic resistant bacteria Karl Ochs Page 9 of 12 reported to be effective to this bacteria in some countries. For E.coli the use of Fluoroquinolones and quinolones has been ineffective in some countries (7). Example of past examples of poor handling of situation The emergence and spread of antibiotic resistance has been accelerated by genetic changes. Abuse and misuse of antibiotics has also contributed to this emergence. Examples where poor handling of situation has occurred is where people with viral infections like flu are given growth promoters found in fish and other animals. Antimicrobial resistant bacteria are found in animals, food and the environment that we live in. Poor infection control and improper handling of food have also contribute to antimicrobial resistance (8). Example of some steps taken According to the Centre for Disease Control and Prevention, patients and healthcare providers must work with policy makers in ensuring that effective strategies are put in place for ensuring that resistance to antibiotics is reduced. Patients should take antibiotics as directed by physicians. They should take those prescriptions that are only prescribed to them and not for other people. Hygiene practices should be ensured between the healthcare providers and patients (8). Antibiotic resistant bacteria Karl Ochs Page 10 of 12 Conclusion In conclusion, antibiotics resistance has been a challenge effacing humanity since the first antibiotic, Penicillin was discovered in 1928.Despite the major changes have been made on the penicillin beta lactam ring, bacteria have also developed mechanism of resistant to counter that change. Resistance mainly occurs through mutations at the site of action of the antibiotic. The main difference between gram positive and gram negative is the thickness of the peptidoglycan layer and this can be seen through Gram staining. Gram negative bacteria such as E.coli have been found to be more resistant to penicillin than other bacteria. Theories have been developed to explain the cause of antibiotic resistance; they are vertical gene and horizontal gene transfer. To reduce the rate at which resistance to antibiotics occurs, the use of antibiotics should be restricted to serious cases where it has been confirmed that a person has a bacterial infection. The use of feeds fortified with antibiotics for broilers also contribute to resistance when they are taken by humans over a long period of time. Antibiotic resistant bacteria Karl Ochs Page 11 of 12 List of References 1. Coates, A. Antibiotic resistance; Springer: Heidelberg, 2012. 2. Bacterial Resistance to Antibiotics http://textbookofbacteriology.net/resantimicrobial_3.html (accessed Oct 4, 2016). 3. Bonomo, R.Watkins, R. Antibiotic Resistance; Elsevier Health Sciences: Saintt Louis, 2016. 4. Flynn, E. Cephalosporins and penicillins: chemistry and biology; Academic Press: New York, 1972. 5. Jones, G.Dever, S. The gram stain; U.S. Dept. of Health and Human Services, Public Health Service, Centers for Disease Control: Atlanta, Ga., 1984. 6. Understanding antibiotic resistance; eScholarship, University of California, 2014. 7. (http://www.who.int/mediacentre/factsheets/fs194/en/). (accessed Oct 5, 2016). 8. Stewart, G.Holt, R. BMJ 1963, 1, 308-311. Antibiotic resistant bacteria Karl Ochs Page 12 of 12