Selective toxicity Antimicrobial Drugs Chapter 20 BIO 220 Drugs must work inside the host and harm the infective pathogens, but not the host Antibiotics are compounds produced by fungi or bacteria that inhibit or kill competing microbial species Alexander Fleming Credited with the discovery of penicillin (1928) Fleming sorted through many petri plates inoculated with Staphylococcus aureus One plate had mold on it, and the mold juice seemed to inhibit bacterial growth The mold was Penicilliumnotatum, and the substance was dubbed penicillin 1
Penicillum Howard Florey and Ernst Chain and their colleagues at Oxford University improved the purification of penicillin (1939) Florey carried out experiments showing that penicillin protected mice against Streptococci (1940) Albert Alexander was the first human to receive the Oxford penicillin (1941) Production eventually shifted to the United States Spectrum of antimicrobial activity Narrow spectrum Broad spectrum Modes of antibacterial drug action Fig. 20.2 2
Inhibition of cell wall synthesis Penicillinscontain a β lactam ring Prevent the crosslinkage of peptidoglycan Only actively growing cells are affected Fig. 20.6 Penicillins Natural Produced by Penicillium Penicillin G and V most commonly used Effective against staphylococci, streptococci, and certain spirochetes (narrow spectrum) Susceptible to penicillinases (β lactamases) Semisynthetic Penicillins Some initially resistant to penicillinases, but not so much now Methicillin MRSA Extended spectrum Amoxicillin, ampicillin Carboxypenicillins Ticarcillin Activity against Pseudomonas aeruginosa Fig. 20.8 3
Inhibitors of cell wall synthesis Carbapenems(β-lactam, broad spectrum) Doripenem effective against Pseudomonas Monobactams (lacks traditional β-lactam ring, affects only certain gram negative bacteria) Effective against E. coli and pseudomonads Cephalosporins Polypeptide antibiotics Bacitracin (gram positive) Vancomycin Used to treat MRSA, now VRE Fig. 20.9 Antimycobacterial antibiotics Work on cell walls of Mycobacterium Isoniazid effective against Mycobacterium tuberculosis Inhibits synthesis of mycolic acids Ethambutol Inhibits incorporation of mycolic acid into the cell wall 4
Inhibitors of protein synthesis Chloramphenicol Inhibits formation of peptide bonds by reacting with the 50S portion of the prokaryotic ribosomes Broad spectrum Small molecular size Suppresses red bone marrow activity Fig. 20.10 Fig. 20.4 Inhibitors of protein synthesis cont. Aminoglycosides Changes the shape of the 30S subunit of prokaryotic ribosome, causing mrna to be misread Activity against gram-negative bacteria Can impact hearing and kidney function Streptomycin (tuberculosis) Gentamicin (Pseudomonas) Inhibitors of protein synthesis cont. Tetracyclines Broad spectrum Interfere with attachment of trna to the ribosome at the 30S subunit, thereby preventing the addition of amino acids Used to treat UTIs, chlamydia, syphilis, gonorrhea, and rickettsial infections Suppresses normal microbiota Side effects teeth discoloration, liver damage 5
Inhibitors of protein synthesis cont. Glycylcyclines(similar to tetracyclines, inhibits the effects of rapid efflux, useful against MRSA) Macrolides (narrow spectrum) - erythromycin Streptogramins- VRE Oxazolidinones - VRE Injury to the plasma membrane Alterations to plasma membrane permeability (polypeptide antibiotics) Some antifungals (ketaconazole, amphotericin B) interfere with sterol synthesis or binds directly to fungal sterols in the PM to disrupt membrane integrity Fig. 20.12 Sulfonamides (sulfa drugs) Some of the first antimicrobials Bacteriostatic Sulfa drugs are structurally similar to a folic acid precursor called para-aminobenzoic acid (PABA) These drugs competitively bind to an enzyme and ultimately block folic acid production (and thus affect synthesis of proteins, DNA, and RNA) 6
Synergism and Antagonism Fig. 20.13 Fig. 20.23 7
How do you know if a pathogen is sensitive to a specific drug? Diffusion methods Disk diffusion method (Kirby Bauer) Zone of inhibition measured Broth dilution tests Compare measurement to a standard table for that drug to determine whether the microbe is resistant, susceptible, or intermediate Fig. 20.17 E test measures MIC Broth dilution tests Fig. 20.18 Wells that do not show growth can be cultured in broth or on agar free of drug. If growth occurs, just bacteriostatic. Fig. 20.19 MBC = minimal bactericidal concentration 8
Resistance to antimicrobial drugs When first exposed to a new antibiotic, the susceptibility of microbes tends to be high The relatively few cells that survive are called persistercells, and likely have some genetic characteristic that protects them These genetic mutations can be spread horizontally among bacteria by conjugation, transduction, use of plasmids or transposons Superbugsare resistant to large numbers of antibiotics Enzymatic destruction/inactivation Mainly affects naturally-produced rather than synthetically-produced antibiotics β-lactamase (many variations) S. aureus, S. pneumoniae Mechanisms of resistance Development of antibiotic resistance Fig. 20.20 Fig. 20.21 9
Antibiotic misuse Antibiotics given for inappropriate uses Dose regimens too short Patients fail to finish medication, save for the next time around Patients take meds prescribed to someone else Administration of narrow spectrum vs. broad spectrum antibiotics Use in animal feed as growth enhancers 10