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3. Inhibition f nucleic acid synthesis Sulfonamides & Trimethoprim Inhibit the synthesis of folic acid the main donor of the methyl groups that are needed for synthesis of adenine, guanine and thymine. A combination of both is often used because bacteria resistant to one drug will often be inhibited by the other. Quinolones Inhibit DNA synthesis by blocking the DNA gyrasethe enzyme that unwinds DNA strands so that they can replicate. They are a family of drugs. Rifampin Inhibits RNA synthesis in bacteria by blocking RNA polymerase, which synthesizes RNA. 4. Altering cell membrane function Anti-fungal drugs are the most important in this category, because fungal cell membranes contain ergosterol, while human cell membranes have cholesterol. Bacteria, with exception of Mycoplasma, don’t have sterols in their membranes and thus are resistant to these drugs. Amphotericin B Disrupts fungal cell membrane by binding to the site of ergosterol in the membrane. It is used to treat systemic fungal infection, but it has side effects, especially on kidneyAzoles Are antifungal drugs that inhibit ergosterol synthesis. The azole family is useful in systemic as well as skin and mucous membrane infections. 5. Additional drug mechanisms Isoniazid Inhibits the synthesis of mycolic acid, a long chain fatty acid found in cell of mycobacterium. It is a prodrug that requires a bacterial peroxidase (catalase) to activate the isoniazid to become the metabolite that inhibits mycolic acid synthesis. Isoniazid is the most important drug in treatment of tuberculosis + other mycobacterial diseases. Mitronidazole Is effective against bacteria and certain protozoa because it acts on electron sink it takes away the electrons the organism needs to survive. It also forms toxic intermediates which damage DNAzoles Are antifungal drugs that inhibit ergosterol synthesis. The azole family is useful in systemic as well as skin and mucous membrane infections. 5. Additional drug mechanisms Isoniazid Inhibits the synthesis of mycolic acid, a long chain fatty acid found in cell of mycobacterium. It is a prodrug that requires a bacterial peroxidase (catalase) to activate the isoniazid to become the metabolite that inhibits mycolic acid synthesis. Isoniazid is the most important drug in treatment of tuberculosis + other mycobacterial diseases. Mitronidazole Is effective against bacteria and certain protozoa because it acts on electron sink it takes away the electrons the organism needs to survive. It also forms toxic intermediates which damage DNA. Chemoprophylaxis These antimicrobial drugs are also used to prevent infectious diseasesA1They are given mainly in 3 circumstances: - To prevent surgical wounds from getting infected - To prevent opportunistic infections in immunocomprised patients - To prevent infections in those known to have been exposed to pathogens that can cause serious infectious diseases3. Bacterial resistance to antibacterial drugs: significance and mechanisms of action. The 4 mechanisms of antibiotic resistance are: 2) Enzymatic degradation of the drug 3) Modification of the drugs’ target 4) Reduced permeability of the drug 5) Active export of the drug Most drug resistance is the result of a genetic chance in the organism, caused either by a chromosomal mutation or acquisition of a plasmid or transposon. Genetic basis of resistance 1. Chromosomal mutation Either changes the target of the drug so the drug won’t be able to bind, or it changes the membrane so that the drug doesn’t penetrate well into the cell. This occurs at low frequency, affecting only one drug or one family of drugs. 2. Plasmids Cause drug resistance by encoding enzymes that degrade or modify the drug This happens at higher frequency, affecting multiple drugs. 3. Transposons Are small pieces of DNA that move from one site on the bacterial chromosome to another or from one bacterial chromosome to plasmid DNA. They often carry drug resistant genes. Non genetic basis of resistance Non genetic reason why bacteria may not be inhibited by antibiotics are that drugs may not be able to reach the bacteria located in the middle of an abscess and also that certain drugs, like penicillin don’t affect bacteria that are growing. The presence of foreign bodies also makes it more difficult to achieve a successful antibiotic treatment. Specific mechanism of resistance Resistance to penicillin and cephalosporins is mediated by 3 mechanisms: 2) Degradation by ß-lactamase (THE MOST IMPORTANT MECH.!) 3) Mutation in genes for penicillin binding proteins 4) Reducing permeability Antibiotic sensitivity testing The minimal inhibitory concentration (MIC) is the lowest concentration of drug that inhibits the growth of the bacteria isolated from the patient. In this test though, it isn’t known if the inhibited bacteria have been killed or just stopped growing. The minimal bactericidal concentration (MBC) is the lowest concentration of drug that kills the bacteria isolated from the patient. In certain diseases, like endocarditis, it is important to use a concentration of drug that is bactericidal. Use of antibiotic combination Two or more antibiotics are used under certain circumstances, like in life threatening infections before the cause has been identified, to prevent the emergency of resistant bacteria during prolonged treatment regimes, and to achieve a synergic effect. Synergism: when the effect of two drugs together is significantly higher than the sum of the effect of the two drugs alone. Antagonism: when the effect of the two drugs together is significantly lower than the effect of the effective drug Alone .