Antimicrobial Agents Lecture Notes PDF

ANTIMICROBIAL AGENTS GEN VETERINARY MICROBIOLOGY  2 ANTIBIOTICS  An antimicrobial substance produced by a living microorganism  Pasteur and Joubert in 1877 first reported some common airborne contamina...

ANTIMICROBIAL AGENTS GEN VETERINARY MICROBIOLOGY  2 ANTIBIOTICS  An antimicrobial substance produced by a living microorganism  Pasteur and Joubert in 1877 first reported some common airborne contaminants that had a lethal effect on Bacillus anthracis  Alexander Fleming in 1929, observed that the fungus Penicillium notatum on a plate strongly inhibited the growth of staphylococci; carried out a crude plate susceptibility test  In 1940, Chain, Florey and associates succeeded in obtaining preparations from Penicillium that had a high antibacterial therapy but low toxicity for humans and animals  After discovery of penicillin, extensive search for antibiotic began  Richest source of antibiotics species of Streptomyces,  3 MECHANISM OF ACTION Classes Based on General Effects on Bacteria 1. Bactericidal  Have rapid lethal action  Ex. Penicillin, streptomycin, cephalosporin, polymyxin, neomycin, erythromycin in high concentrations 2. Bacteriostatic  Inhibit the growth of microorganisms  Ex. Tetracyclines, sulfonamides and chloramphenicol  Some maybe both bactericidal and bacteriostatic 1. Inhibition of growth by antimetabolites (Molecular mimicry) a. Sulfonamides  Bacteriostatic  Inhibit growth but do not kill  Effective against growing and proliferating bacteria but not against dormant ones  For many bacteria, para-aminobenzoic acid (PABA) is essential metabolite in the synthesis of folic acid which is required in synthesis of purines  Sulfonamides structural analogues of PABA (para-amino benzene sulfonamide/PABS) therefore can compete with it forming nonfunctional analogues of folic acid  Some bacteria cannot synthesize folic acid but require it  Hence not inhibited by sulfonamides  Excess PABA released during extensive tissue destruction counteracts inhibiting action of sulfonamides  PABA maybe added to culture media to isolate bacteria from animals treated with sulfonamide  Sulfonamides maybe combined with diaminopyrimidines (trimethoprim, ormetoprim, etc.) to enhance activity with bactericidal consequences  Trimethoprim blocks the formation of folic acid by inhibiting dihydrofolic acid reductase, an enzyme essential for the formation of tetrahydrofolate from dihydrofolate  Mutant resistance occurs with sulfonamides but most resistance caused by an R factor (plasmid) b. Sulfones  Also structural analogues of PABA and mode of action similar to sulfonamides  Relatively toxic with limited antimicrobial spectrum 2. Inhibition of cell wall synthesis  Peptidoglycans of bacterial cell wall unique  Antimicrobial drugs that inhibit synthesis of glycopeptides effective clinically a. Penicillins  Inhibit synthesis of cell walls of growing susceptible bacteria  Bacterial protoplasm increases and eventually bursts the cytoplasmic membrane resulting in lysis and death  If bacteria are growing in a medium of high osmotic  Forms called protoplasts (gram positive) and spheroplasts (gram negative) with intact cytoplasmic membrane are formed  Inhibits enzyme responsible for crosslinking between layers of peptidoglycan  Most active against gram positive but also active against a number of gram negative bacteria  Of value in treatment are penicillin G (benzyl penicillin) given IM and penicillin V (phenoxymethyl penicillin) given orally  Procaine added to penicillin to delay absorption  Adding side chains to naturally occurring 6-amino penicillanic acid prevents degradation of B-lactam ring by penicillinase (B-lactamase)  (MRSA) which is nosocomially acquired c. Cephalosporins  Derived from Cephalosporium mold  Chemically resembles penicillin, mode of action similar to that of penicillin and bactericidal with low toxicity 1. Resistance to penicillinase 2. Not as allergenic as penicillin 3. Broad spectrum of activity, can be used against staphylococci, streptococci and a wide spectrum of gram negative  Ex. cephalexin, cefadroxil d. Bacitracin – Bacillus subtilis e. Vancomycin - streptomycetes f. Carbapenems broad spectrum, semisynthetic derivative produced by Streptomyces spp 3. Inhibition of protein synthesis a. Aminoglycosides  Derived from Micromonospora spp.(gentamicin) or from Streptomyces spp (streptomycin, neomycin, tobramycin, kanamycin)  Bind to 30S ribosomal subunit resulting in miscoding of proteins and inhibition of peptide elongation  Resistance to aminoglycosides 1) Impaired ribosomal binding 2) Impaired transport across cell membrane 3) Aminoglycoside-altering enzymes – enzymes involved in inactivation of the drug b. Tetracycline  Derived from Streptomyces  Naturally occurring chlortetracycline, oxytetracyline, demethylchlortetracycline; doxycycline, tetracycline semisynthetic derivative  Binding with 30S causing inhibition of function of tRNA  Bacteriostatic and mode of action reversible  Broad spectrum  Superinfection with Candida albicans or S. aureus complication after treatment with tetracycline; liver damage, inhibit growth of bones and teeth  Plasmid related R factor c. Chloramphenicol – Chloromycetin  Broad specrum, from streptomycete  Bacteriostatic, binds to 50S ribosomal subunit  Prolonged administration results to severe depression of bone marrow d. Macrolides  Erythromycin, tylosin, tilmicosin  Derived from streptomycetes and binds to 50S  Advanced generation macrolides azithromycin, clarithromycin e. Lincosamides  Clindamycin, lincomycin 4. Impairment of cell membrane function  Damage of cell membrane results to loss of osmotic control causing leakage of potassium ions and other components, eventually death 5. Inhibition of nucleic acid function a. Quinolones  Synthetic analogues of nalidixic acid  Urinary antiseptic  Inhibit DNA gyrase reducing the supercoiling of chromosomal DNA around an RNA core  Loosely coiled DNA degraded into small, nonfunctional fragments by exonucleases  Bactericidal  Resistance due to: 1) Change in outer membrane permeability 2) Alteration in A subunit of DNA gyrase b. Nitrofurans derivative – nitrofurazone  Inhibit bacterial enzymes and damage DNA c. Nitromidazole – metromidazoles  Against anaerobic bacteria d. Rifampin Mechanisms of drug resistance 1. Adoption by organism of an alternative metabolic pathway 2. Production of enzyme that destroys antibiotic 3. Change of permeability and decrease uptake of drug 4. Altered structural target HAVE A GREAT DAY! THANK YOU!