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Batterjee Medical College Batterjee Medical College Antimicrobial Drugs: Mechanism of Action Dr. Manal El Said Head of Microbiology Department Batterjee Medical College Antimicrobial Drugs: Mechanism of Action: Introduction • There are four major sites in bacterial cell that serve as basis for action of effective drugs: 1.Cell wall 2. Ribosomes 3. Nucleic acids 4. Cell membrane Batterjee Medical College Antimicrobial Drugs: Mechanism of Action: Introduction Batterjee Medical College Antimicrobial Drugs: Mechanism of Action: Introduction Mechanism of Action Drugs Inhibition of cell wall synthesis Inhibition of cross-linking (transpeptidation) -Penicillins of peptidoglycan -Cephalosporins - Imipenem - Aztreonam, - Vancomycin Inhibition of other steps in peptidoglycan - Cycloserine synthesis - Bacitracin Antifungal activity inhibition of β-glucan - Caspofungin synthesis Inhibition of protein synthesis Action on 50S ribosomal subunit - Chloramphenicol - erythromycin - clindamycin - linezolid Action on 30S ribosomal subunit -Tetracyclines - Aminoglycosides Batterjee Medical College Antimicrobial Drugs: Mechanism of Action: Introduction Mechanism of Action of Important Antibacterial and Antifungal Drugs Drugs Mechanism of Action Inhibition of nucleic acid synthesis Inhibition of nucleotide synthesis Sulfonamides, trimethoprim Inhibition of DNA synthesis Quinolones, e.g., ciprofloxacin Inhibition of mRNA synthesis Rifampin Alteration of cell membrane function Antibacterial activity Antifungal activity Polymyxin, daptomycin Amphotericin B, nystatin, terbinafine, azoles, e.g., itraconazole Other mechanisms of action 1. Antibacterial activity 2. Antifungal activity Isoniazid, metronidazole, ethambutol, pyrazinamide Griseofulvin, pentamidine Batterjee Medical College Antimicrobial Drugs: Mechanism of Action: Introduction Selective toxicity • It is selective inhibition of growth of microorganism without damage to host. • It is achieved by exploiting differences between metabolism & structure of microorganism & human cells. • Penicillins & cephalosporins are effective antibacterial agents prevent synthesis of peptidoglycan inhibiting growth of bacterial (not human cells). Batterjee Medical College Antimicrobial Drugs: Mechanism of Action: Introduction Broad-spectrum antibiotics • Broad-spectrum antibiotics are active against several types of microorganisms e.g., tetracyclines are active against many gram-negative rods, chlamydiae, mycoplasmas, & rickettsiae. Narrow-spectrum antibiotics • Narrow-spectrum antibiotics are active against one or very few types, e.g., vancomycin is used against certain gram-positive cocci, staphylococci & enterococci. Batterjee Medical College Antimicrobial Drugs: Mechanism of Action: Introduction Bactericidal drug • Bactericidal drug kills bacteria Bacteriostatic drug • Bacteriostatic drug inhibits their growth but does not kill them - Bacteria can grow again when drug is withdrawn - Host defense mechanisms, such as phagocytosis, are required to kill bacteria. Batterjee Medical College Antimicrobial Drugs: Mechanism of Action: Introduction Batterjee Medical College Antimicrobial Drugs Chemoprophylaxis • Antimicrobial drugs are used to prevent infectious diseases as well as to treat them. • They are given primarily in three circumstances: 1. to prevent surgical wound infections 2. to prevent opportunistic compromised patients infections in immuno- 3. to prevent infections in those known to be exposed to pathogens that cause serious infectious diseases. Batterjee Medical College Antimicrobial Drugs: Probiotics • In contrast to chemical antibiotics, probiotics are live, nonpathogenic bacteria that may be effective in treatment or prevention of certain human diseases. • The suggested basis for possible beneficial effect lies in: 1. providing colonization resistance by which nonpathogen excludes pathogen from binding sites on mucosa 2. enhancing immune response against pathogen 3. reducing inflammatory response against pathogen. Batterjee Medical College Antimicrobial Drugs: Probiotics • Oral administration of live Lactobacillus rhamnosus strain GG significantly reduces number of cases of nosocomial diarrhea in young children. • Yeast Saccharomyces boulardii reduces risk of antibioticassociated diarrhea caused by Clostridium difficile. • Adverse effects are few; however, serious complications have arisen in highly immunosuppressed patients and in patients with indwelling vascular catheters. Batterjee Medical College Antimicrobial Drugs: Probiotics Batterjee Medical College Antimicrobial Drugs: Probiotics Batterjee Medical College Antimicrobial Drugs: Mechanism of Action Dr. Manal El Said Head of Microbiology Department Batterjee Medical College Antimicrobial Drugs: Resistance Four main mechanisms of antibiotic resistance are: (1) enzymatic degradation of drug (2) modification of drug's target (3) reduced permeability of drug (4) active export of drug. • Most drug resistance is result of genetic change in organism, caused either by: - Chromosomal mutation - Acquisition of plasmid or transposon. Batterjee Medical College Antimicrobial Drugs: Major Mechanisms of Bacterial Resistance Batterjee Medical College Antimicrobial Drugs: Resistance: Specific Mechanisms of Resistance Enzyme destroy or inactivate antibiotic Bacterial resistance to antibiotics—producing an enzyme to destroy or inactivate the antibiotic. This animation can be found at The Grapes of Staph: Doc Kaiser's Microbiology Website, http://student.ccbcmd.edu/~gkaiser/goshp.html. Batterjee Medical College Antimicrobial Drugs: Resistance: Specific Mechanisms of Resistance Altered Enzyme Bacterial resistance to antibiotics—producing an altered enzyme to which the antibiotic no longer binds. This animation can be found at The Grapes of Staph: Doc Kaiser's Microbiology Website, http://student.ccbcmd.edu/~gkaiser/goshp.html. Batterjee Medical College Antimicrobial Drugs: Resistance: Specific Mechanisms of Resistance Altered ribosomal subunit Bacterial resistance to antibiotics—producing an altered ribosomal subunit to which the antibiotic no longer binds. This animation can be found at The Grapes of Staph: Doc Kaiser's Microbiology Website, http://student.ccbcmd.edu/~gkaiser/goshp.html. Batterjee Medical College Antimicrobial Drugs: Resistance: Specific Mechanisms of Resistance Altered porins block passage of antibiotic A bacterium producing altered porins that block passage of the antibiotic through the outer membrane of a gram-negative bacterium. Batterjee Medical College Antimicrobial Drugs: Resistance: Specific Mechanisms of Resistance Altered transport (carrier) protein A bacterium producing an altered transport (carrier) protein that prevents transport of the antibiotic through the cytoplasmic membrane. Batterjee Medical College Antimicrobial Drugs: Resistance: Specific Mechanisms of Resistance Transporter molecules A bacterium producing transporter molecules that pump the antibiotic out of the bacterium. Batterjee Medical College Antimicrobial Drugs: Resistance: Specific Mechanisms of Resistance Greater amounts of the limited enzyme A bacterium producing greater amounts of the limited enzyme being tied up or inactivated by the antimicrobial agent. Although some enzyme is tied up by the drug, there is still enzyme available to react with its substrate and produce end products. Batterjee Medical College Antimicrobial Drugs: Resistance: Genetic Basis of Resistance Chromosomal mutations • Chromosomal mutations typically: - Change target of drug - Change membrane drug does not bind drug does not penetrate into cell. • It occurs at low frequency (1 in 10 million organisms). • It affect only one drug or one family of drugs. Batterjee Medical College Antimicrobial Drugs: Resistance: Genetic Basis of Resistance Plasmids • Plasmids encoding enzymes that degrade or modify drugs. • It occurs at higher frequency • it affects multiple drugs or families of drugs. • Resistance plasmids (R plasmids, R factors) carry two sets of genes: - One set encodes enzymes that degrade or modify drugs - Other encodes proteins that mediate conjugation Batterjee Medical College Antimicrobial Drugs: Resistance: Genetic Basis of Resistance Transposons • Transposons are small pieces of DNA that move: - from one site on bacterial chromosome to another or, - from bacterial chromosome to plasmid DNA. • Transposons often carry drug resistance genes. • Many R plasmids carry one or more transposons. Batterjee Medical College Antimicrobial Drugs: Resistance: Genetic Basis of Resistance Batterjee Medical College Antimicrobial Drugs: Nongenetic Basis of Resistance Nongenetic Basis of Resistance 1. Drugs may not reach bacteria located in center of abscess 2. Certain drugs, such as penicillins, will not affect bacteria that are not growing. 3. Presence of foreign bodies makes antibiotic treatment difficult. Batterjee Medical College Antimicrobial Drugs Selection of Resistant Bacteria by Overuse & Misuse of Antibiotics • Overuse & misuse of antibiotics increase the occurrence of gram-negative rods resistant to multiple antibiotics by enhancing selection of resistant mutants: 1. Some physicians : -Use multiple antibiotics when one would be sufficient -Prescribe unnecessarily long courses of antibiotic therapy -Use antibiotics in self-limited infections. -Overuse antibiotics for prophylaxis before & after surgery. Batterjee Medical College Antimicrobial Drugs Selection of Resistant Bacteria by Overuse & Misuse of Antibiotics 2. In many countries, antibiotics are sold over the counter to general public encourages inappropriate & indiscriminate use of the drugs. 3. Antibiotics are used in animal feed to prevent infections and promote growth in animals in humans. selects for resistant organisms contribute to pool of resistant organisms Batterjee Medical College Antimicrobial Drugs: Antibiotic Sensitivity Testing The minimal inhibitory concentration (MIC) It is lowest concentration of drug that inhibits growth of bacteria isolated from patient NB: it is not known whether inhibited bacteria have been killed or just have stopped growing. The minimal bactericidal concentration (MBC) It is lowest concentration of drug that kills bacteria isolated from patient. Batterjee Medical College Antimicrobial Drugs: Use of Antibiotic Combinations Use of Antibiotic Combinations • Two or more antibiotics are used to: - treat life-threatening infections before cause has been identified, - prevent emergence of resistant bacteria during prolonged treatment regimens - achieve synergistic (augmented) effect. Batterjee Medical College Antimicrobial Drugs: Use of Antibiotic Combinations Use of Antibiotic Combinations Synergistic • Synergistic effect is : effect of two drugs given together is much greater than sum of effect of two drugs given individually. e.g. marked killing effect of combination of penicillin & aminoglycoside on enterococci compared to minor effect of either drug given alone. Batterjee Medical College Antimicrobial Drugs: Use of Antibiotic Combinations Rarely, the effect of the two drugs together is antagonistic, in which the result is significantly lower activity than the sum of the activities of the two drugs alone. Batterjee Medical College Antimicrobial Drugs Batterjee Medical College Bacterial Vaccines Batterjee Medical College Bacterial Vaccines Immunity to certain bacterial diseases can be induced by: • Immunization with bacterial antigens (active immunity) • Administration of preformed antibodies (passive immunity). Batterjee Medical College Bacterial Vaccines Active immunity Active immunity can be achieved by vaccines consisting of: (1) bacterial capsular polysaccharides, bacteria (either killed or live, attenuated) (2) purified proteins isolated from bacteria. toxoids, whole Batterjee Medical College Bacterial Vaccines Active immunity Batterjee Medical College Bacterial Vaccines Active immunity Vaccines containing capsular polysaccharide as immunogen are directed against : •Streptococcus pneumoniae •Haemophilus influenzae •Neisseria meningitidis •Salmonella typhi. Capsular polysaccharide is conjugated to carrier protein to enhance antibody response. Batterjee Medical College Bacterial Vaccines Active immunity •Two vaccines contain toxoids as immunogen: - Diphtheria - Tetanus. • Toxoid is inactivated toxin that has lost its ability to cause disease but has retained its immunogenicity. Batterjee Medical College Bacterial Vaccines Active immunity Two vaccines immunogen: contain purified bacterial proteins as 1-Acellular pertussis vaccine: • Combination with diphtheria & tetanus toxoids • It is recommended for all children. 2-Anthrax vaccine: • Contains purified proteins • It is recommended only for individuals who are likely to be exposed to organism. Batterjee Medical College Bacterial Vaccines Active immunity • BCG vaccine against tuberculosis contains live, attenuated Mycobacterium bovis & is used in countries where the disease is endemic. • One of vaccines against typhoid fever contains live, attenuated Sal. typhi. • Vaccines against cholera, plague, typhus, & Q fever contain whole killed bacteria. • These vaccines are used only to protect those likely to be exposed. Batterjee Medical College Bacterial Vaccines Passive Immunity • Antitoxins for prevention & treatment of : - Tetanus - Botulism - Diphtheria. • These three diseases are caused by exotoxins. • Antitoxins (antibodies against exotoxins) bind to exotoxins & prevent their toxic effects, i.e., they neutralize toxins. Batterjee Medical College Bacterial Vaccines Passive–Active Immunity • This involves providing both immediate (but short-term) protection in form of antibodies & long-term protection in form of active immunization. • e.g. prevention of tetanus in unimmunized person who has sustained contaminated wound. - Both tetanus antitoxin & tetanus toxoid should be given. -They should be given at different sites so that antibodies in antitoxin do not neutralize toxoid.