Antibiotics. Antimicrobial Drugs. Alexander Fleming 10/18/2017

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1 Antibiotics Antimicrobial Drugs Chapter 20 BIO 220 Antibiotics are compounds produced by fungi or bacteria that inhibit or kill competing microbial species Antimicrobial drugs must display selective toxicity, which means they must work inside the host and harm the infective pathogens but not the host 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 Penicillium notatum, and the substance was dubbed penicillin 1

2 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 i.e. Penicillin G Used when causative microorganism is known Broad spectrum i.e. Tetracycline Destroy some of normal microbiota of host, can lead to overgrowth of other microbes that can become opportunistic pathogens (superinfection) (i.e. Candida albicans, Clostridium difficile) Modes of antibacterial drug action Fig Antibiotics are either bacteriostatic or bacteriocidal. 2

3 Inhibition of cell wall synthesis Penicillins contain a β lactam ring Prevent the crosslinkage of peptidoglycan (synthesis of intact peptidogycan) Only actively growing cells are affected Bactericidal Fig Fig Penicillins Natural Produced by Penicillium Penicillin G (injected) 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 methicillin-resistant Staphylococcus aureus Extended spectrum Amoxicillin, ampicillin Not resistant to penicillinases Carboxypenicillins Carbenicillin, ticarcillin (greater activity against gram (-) bacteria) Activity against Pseudomonas aeruginosa 3

4 Inhibitors of cell wall synthesis Carbapenems (β-lactam, broad spectrum) Doripenem effective against Pseudomonas, not MRSA or Enterococcus faecium Monobactams (lacks traditional β-lactam ring, affects only certain gram negative bacteria) Effective against E. coli and pseudomonads Cephalosporins Modified β-lactam ring Polypeptide antibiotics Bacitracin (gram positive) (-) synth linear strands of peptid. Vancomycin Used to treat MRSA, now VRSA, VRE 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 Rifampin Suppresses bacterial RNA synthesis Fig

5 Inhibitors of protein synthesis Chloramphenicol (bacteriostatic) Inhibits formation of peptide bonds by reacting with the 50S portion of the prokaryotic ribosomes Broad spectrum Small molecular size Fig Suppresses red bone marrow activity Clindamycin, metronidazole anaerobic activity Fig Inhibitors of protein synthesis cont. Aminoglycosides (bactericidal) 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, some gram negative infections), administered IM Gentamicin (Pseudomonas) Inhibitors of protein synthesis cont. Tetracyclines (bacteriostatic) 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

6 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, MRSA 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 Sulfonamides (sulfa drugs) bactericidal Gram-positive infections mycobacterial infections Some of the first antimicrobials Completely synthetic 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) UTIs 6

7 Work synergistically Synergism and Antagonism Broad spectrum of action Less resistance Fig Fig 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

8 E test measures MIC Broth dilution tests Fig Does not determine if drug is bacteriostatic or bactericidal. Wells that do not show growth can be cultured in broth or on agar free of drug. If growth occurs, just bacteriostatic. Useful for determining MIC and MBC. Fig MBC = minimal bactericidal concentration 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 persister cells, and likely have some genetic characteristic that protects them These genetic mutations can be spread horizontally and vertically among bacteria Resistance can also be carried on plasmids or transposons Superbugs are resistant to large numbers of antibiotics Development of antibiotic resistance Fig

9 Mechanisms of resistance Enzymatic destruction/inactivation Mainly affects naturally-produced rather than synthetically-produced antibiotics β-lactamases (>1000 variations) S. aureus, S. pneumoniae Fig Mechanisms of resistance 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 Fig

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