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Antibiotics are substances produced by microorganisms that can either destroy or inhibit the growth of Gram-positive bacteria.(3) Antibiotics are produced by microorganisms, usually by bacteria but also by fungi, e.g. penicillin, perhaps the most famous of all antibiotic drugs, and others such as fusidic acid, cephalosporin and griseofulvin.(3)
Discovery of antibiotics
There is a consistent need for new antibacterial drugs due to the inevitable development of resistance that pursue the introduction of antibiotics to the clinic.(9) When a new class of antibiotic is introduced, it is effective at first, but will ultimately select for survival of the small fraction of bacterial populations that have a built in or obtain resistance mechanism.(9) Pathogens that are resistant to numerous drugs arise around the globe, so how strong are antibiotic discovery processes.(9)
The key to developing more useful penicillin's was the discovery of the core of the penicillin molecule.(3) To this principle chemists can add a whole family of side chains to produce molecules with different properties.(3) These antibiotics are called semi-synthetic because the raw material is produced naturally and is then chemically modified. Their creation has ushered in a new era of therapy.(3)
Many of the most useful antibiotics are semi-synthetic e.g. cephalosporins, and the carbapenems.(1) That is, chemists alter the structure of a naturally produced substance to make it even more effective.(1) Today, some antibiotics that were originally natural, are made entirely synthetically e.g. sulfamethoxazole, sulfaisodimidine sulfacetamide, and sulfadoxine.(1) These antibiotics are now made in labs from cheap, abundant chemicals rather than by laboriously growing large amounts of the mould in cultures (1)
What do Antibiotics do and how do they work?
There are many different types of antibiotics. Most work by inhibiting a biochemical pathway in the target microorganism, blocking its growth.(5) Antibiotics are not equally effective against all Grampositive bacteria. An antibiotic will affect only those which have a particular property in common.(5) Antibiotics work by interfering with some essential operation of the bacterial cell, such as:
Vancomycin and other antibiotics interfere with the making of the bonds that strengthen the bacterial cell walls.(1) These cell walls contain long, linear polymers called peptidoglycans, made up of alternating molecules of modified glucose residues with short peptide chains attached.(1) Peptidoglycan molecules are cross linked by further peptide chains, the detail of which varies from species to species.(1) Vancomycin and related antibiotics inhibit the synthesis and assembly of the peptide cross links, ultimately weakening the bacteria cell wall, leading to cell death. Because these particular antibiotics work during the synthesis of the cell wall, these antibiotics are active against bacteria only when they are growing.(1) Although peptidoglycans are a vital constituent of almost all bacteria, they are absent from mammalian cells. That is why antibiotics such as penicillin will kill the bacteria but not the patient. (1)
Tetracycline and other antibiotics, interfere with the protein-making apparatus of bacterial cells. They often bind to the ribosomes, the organelles that oversee the joining of amino acids to form proteins.(1) Although protein synthesis is similar in outline in mammals and bacteria, the detailed differences are significant and they allow antibiotics to bind only top ribosomes from bacteria. However, some of these antibiotics such as tetracycline binds equally well to both types of ribosomes, but is taken up by bacterial cells and excluded from mammalian cells.(1)
Rifampicin and the anthracyclines are antibiotics that interfere with nucleic acid synthesis. As with protein synthesis, it is the detailed differences between bacterial and mammalian cells that form the basis for selective action. Rifampicin, for example binds selectively to RNA polymerase in bacteria but not in mammals.(1)
Antibiotics that are used primarily against fungi and bacteria, work by damaging cell membranes. Cell membranes of fungi contain ergosterol and those of mammalian cells contain cholesterol.(1)
Many pathogens become resistant to drugs by for example developing enzymes that degrade a drug or inactivate it. Drugs usually work by inhibiting a particular step in a biochemical pathway in the microorganisms. If an alternative pathway is available, or is evolved, the drug will no longer work. Unfortunately treating infections with drugs selects for those organisms that can resist them. These survive treatment, even though 99.9 % of their fellow invaders may be killed or inhibited. The survivors then continue to multiply. Many of these are destroyed by body defences but some may escape and continue to cause infections. Drug resistance plasmids can often be transferred between bacteria of the same and different species. (5)
Mutations in bacterial DNA can cause antibiotic resistance. Mutations are changes in the base sequence of an organisms DNA. If a mutation occurs in the DNA of a gene it could change the protein and cause a different characteristic. Some mutations in bacterial DNA means that the bacteria are not affected by a particular antibiotic anymore i.e. they develop antibiotic resistance. (7)
Antibiotic resistance can be passed on vertically. Vertical gene transmission is where genes are passed on during reproduction. Bacteria reproduce asexually, so each daughter cell is an exact copy of the parent. This means that each daughter cell has an exact copy of the parent cell gene, including any that passed on antibiotic resistance. Genes for antibiotic resistance can be found in the bacterial chromosome or in plasmids. The chromosome and any plasmids are passed on to the daughter cells during reproduction. (7)
Genes for resistance can also be passed on horizontally this happens when two bacteria join together in a process called conjugation and a copy of plasmid is passed from one cell to another. Plasmids can be passed on to a member of the same species or a totally different species. (7)
Methicillin Resistant Staphylococcus aureus (MRSA) is a strain of Staphylococcus aureus bacterium that has evolved to be resistant to a number of commonly used antibiotics, including Methicillin. (7) Staphylococcus aureus causes a range of illnesses including life threatening diseases such as meningitis and septicaemia.(7) The major problem with MRSA is that some strains are resistant to nearly all antibiotics that are available.(7)
Vancomycin is an antibiotic used in the treatment of infections caused by Gram-positive bacteria. It has traditionally been reserved as a drug of 'last resort', used only after treatment with other antibiotics had failed. (8) It is particularly effective against Gram-positive bacteria and has been known to be active against resistant strains of MRSA. (10)
As mentioned before, the mechanism of action of Vancomycin inhibits the cell wall biosynthesis in Gram-positive bacteria.(10) In a Gram-positive bacterium, the cell wall is made up of peptidoglycan, a polysaccharide that contains repeating sugar units.(10) The two sugars are called NAG and NAM.(10) In a Gram-positive bacteria, the peptidoglycan layer is 20-80 nanometres thick.(10) Lipoteichoic acids connect the peptidoglycan layer to the plasma membrane. The NAM and NAG sugars are made in the cytoplasm as UDP derivatives.(10) A pentapeptide chain is added to NAM.(10) Each sugar is added to a bactoprenal carrier, then one NAM-NAG unit is transferred across the membrane and added to the growing peptidoglycan chain.(10) The peptide chains are cross-linked to strengthen the entire structure.(10) Vancomycin binds to the end of the pentapeptide chains of growing peptidoglycan polymers.(10) This binding prevents the transpeptidation reactions that cause cross linking between neighbouring peptidoglycan chains, resulting in a weaker cell. (10)
However, bacteria such as Staphylococcus aureus have started developing resistance to Vancomycin as well, leading to Vancomycin resistant staphylococcus aureus (VRSA), and therefore leading to use of other antibiotics e.g. linezolid hence until now Vancomycin was the last resort. However Vancomycin is no longer the last drug of resort, other dugs such as Linezolid are used after Vancomycin fail to kill all the bacteria.(11)
Linezolid binds to the ribosome and inhibits microbial protein synthesis. The antibiotic reversibly blocks the formation of protein by binding to the 23S ribosomal RNA (rRNA) of the 50S ribosomal subunit, near the interface formed with the 30S ribosomal subunit. Invitro studies have confirmed that linezolid has good activity against most medically important Gram-positive bacteria.(11)
The activity of antibiotics can be classified as bactericidal i.e. causing death of bacteria or bacteriostatic i.e. preventing bacterial growth. The implications of bactericidal action in
serious Gram-positive infections that lead to life-threatening disease in hospitalised patients is the subject of much debate. Bactericidal antibiotics, such as the beta-lactams including vancomycin, are often chosen for treatment of these diseases, particularly for cases of, meningitis, and endocarditis.(11)
The use of antibiotics by Doctors and specialist in hospitals and elsewhere requires them to quickly realise the increasing problems with resistant organisms. This awareness is especially important as there is limited availability of radically new antibiotics. Hence, unessential use of an antibiotic has public-health implications.(11) Physicains e.g. doctors should not give antibiotics for general colds and flu the body's natural defences can fight them off and reserve antibiotics for serious infections, and society should be educated to complete the full course of antibiotics to ensure all the bacteria is dead so cant become resistant to the antibiotics.