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RESISTANCE OF BACTERIA TO ANTIMICROBIAL DRUGS There are many mechanisms by which micro-organisms might exert resistance to drugs: Micro-

organisms produce enzymes that destroy the active drugs(Drug inactivation mechanisms) Micro-organisms may change their permeability to the drug Micro-organisms develop an altered structural target to the drug. Micro-organisms develop an altered metabolic pathway that bypasses the reaction inhibited by the drug. Micro-organisms develop an altered enzyme that can still perform its metabolic function but is much less affected by the drug than the enzyme in the susceptible organism. 1. Micro-organisms produce enzymes that destroy the active drug/ inactivate antimicrobials. - Genes that code for the production of resistant enzymes are carried one on plasmids. Resistant plasmids can code for enzymes responsible for the resistance of several drugs such as Penicillin, sulphonamides, tetracycline, and streptomycin. - Examples of enzymes - lactamases that destroy the beta-lactam ring that forms part of the structure of Penicillin and Cephalosporin -lactamases production is associated with S. aureus Haemophilus influenzae Neisseria gonorrheae Gram negative bacteria resistant to Aminoglycosides produce; Adenylylating Phosphorylating Enzymes that destroys the drug Acetylating Gram negative bacteria that produce a Chloramphenicol acetyltransferase are resistant to chloramphenicol. 2. Micro-organisms may change their permeability to the drug (decreased permeability to a drug) e.g. Tetracycline and polymyxins - bacteria alter their permeability of their cell membranes, making it difficult for antimicrobials to enter. e.g.- Tetracycline accumulates in susceptible bacteria but not in resistant bacteria - Resistance to polymyxins is also associated with a change in permeability to the drugs. - Streptococci have a natural permeability barrier to aminoglycosides (Change in outer membrane that impairs active transport) * The resistance of some bacteria can be due to mechanisms that prevent the drug from entering the cell and acting on its target. Tetra- plasmid encoded protein that pumps the drug out of the cell.

3. Micro-organisms develop an altered structural target for the drug (change of drug receptors) e.g. - Chromosomal resistance to ammo glycosides is associated with the alteration of a specific protein in the 30s sub-unit of the bacterial chromosomes that serves as a binding site in susceptible organisms. - Erythromycin resistant organisms have an altered receptor on the 50s sub-unit of the ribosome, resulting from methylation of a 23s ribosomal RNA. Because most drugs act on a specific target such as protein, RNA, DNA or membrane structure, microbes can circumvent drugs by altering the nature of these targets. Bacteria resistant to rifampicin and streptomycin, the structure of key protein have been altered so that these antibodies can no longer bind. Erythromycin and Clindamycin resistance is associated with an alteration in the 50s ribosomal binding site. Penicillin resistance in Streptococcus pneumoniae and methialin resistance to S. aureus are related to an alteration in binding proteins in the cell wall. Fungi can become resistant by decreasing their synthesis of ergoterol the principle receptor of certain antifungal drugs.

4. Micro-organisms can develop altered metabolic pathways that bypass the reaction inhibited by the drug (changes in metabolic patterns) - Sulphonamide resistant bacteria do not require extra cellular PABA, but like mammalian cells, can utilize preformed folic acid. - The action of anti- metabolites can be circumvented if the microbe develops an alternative metabolic pathway or enzymes. 5. Micro-organisms develop an altered enzyme that can still perform its metabolic function but is much less affected by the drug than the enzyme in the susceptible organism. e.g. Trimethoprin- resistant bacteria, the Dihydrofolic acid reductase is inhibited far less efficiently than the trimethoprin susceptible bacteria. Ref. 1. Jawetz, Melmek and Adenberges medical microbiology, 9th Ed. 2. Foundatons in Microbilogy. Kathleen Talaro and Arthur Talaro 2nd Ed. 1996.