Ch 20 Antimicrobial Drugs Antimicrobial Drugs Chemotherapy The

Ch 20 Antimicrobial Drugs

Antimicrobial Drugs § Chemotherapy: The use of drugs to treat a disease. § Antimicrobial drugs: Interfere with the growth of microbes within a host. § Antibiotic: Of biological origin. Produced by a microbe, inhibits other microbes. § Chemotherapeutic agent: synthetic chemicals § Today distinction blurred many newer "antibiotics" are biological products that are § chemically modified or § chemically synthesized Copyright © 2006 Pearson Education, Inc. , publishing as Benjamin Cummings

Features of Antimicrobial Drugs § Selective toxicity: Drug kills pathogens without damaging the host. § Therapeutic index: ratio between toxic dose and therapeutic dose – or ratio of LD 50 to ED 50 High therapeutic index less toxic § Antimicrobial action – Bacteriostatic vs. bactericidal § Activity Spectrum – Broad-spectrum vs. narrowspectrum § Tissue distribution, metabolism, and excretion – BBB; Unstable in acid; half-life duration Copyright © 2006 Pearson Education, Inc. , publishing as Benjamin Cummings

The History of Chemotherapy § Paul Ehrlich and Sahachiro Hata developed Salvarsan (Arsphenamine) against syphilis in 1910: The concept of chemotherapy to treat microbial diseases was born. § Sulfa drugs (sulfanilamide) discovered in 1935 against gram + bacteria Copyright © 2006 Pearson Education, Inc. , publishing as Benjamin Cummings

The History of Chemotherapy cont. 1928: Fleming discovered penicillin 1940: Howard Florey and Ernst Chain performed first clinical trials of penicillin. Copyright © 2006 Pearson Education, Inc. , publishing as Benjamin Cummings Fig 20. 1

The Sites of Activity in a Bacterial Cell for Various Antibiotics Compare to Fig 20. 2

Antibacterial Antibiotics Inhibitors of Cell Wall Synthesis: Penicillin Natural and semisynthetic penicilins contain β-lactam ring Natural penicillins produced by Penicillium are effective against Gram + cocci and spirochetes Semisynthetic penicillins: made in laboratory by adding different side chains onto β-lactam ring penicillinase resistant and broader spectrum of activity Penicillinase (β-lactamase): bacterial enzyme that destroys natural penicillins Penicillinase resistant penicillins: methicilin replaced by oxacilin and nafcilin due to MRSA Extended-spectrum penicilins: Ampicilin, amoxicilin; new: carboxypenicilins and ureidopenicillins (also good against P. aeruginosa) Copyright © 2006 Pearson Education, Inc. , publishing as Benjamin Cummings

Compare to Fig 20. 8

Cephalosporins Fungi of genus Cephalosporium 4 Generations of cephalosporins Chemical structure and mode of action resembles penicilins Advantages: More stable than penicilins to bacterial -lactamases, broader spectrum used against penicillin-resistant strains. Incidence of cross-sensitivity with penicillin estimated at 5 -16% Copyright © 2006 Pearson Education, Inc. , publishing as Benjamin Cummings

Vancomycin § Glycopeptide from Streptomyces § Inhibition of cell wall synthesis § Used to kill MRSA § Emerging Vancomycin resistance: VRE and VRSA Copyright © 2006 Pearson Education, Inc. , publishing as Benjamin Cummings

Antifungal Drugs § Polyenes, such as nystatin and amphotericin B, for systemic fungal infections. Combine with fungal plasma membrane sterols fungicidal. Nephrotoxic § Griseofulvin from Penicillium. Systemic/oral. Interferes with eukaryotic cell division and is used primarily for superficial dermatophytoses. Copyright © 2006 Pearson Education, Inc. , publishing as Benjamin Cummings

Antiviral Drugs Nucleoside analogs inhibit DNA synthesis § Acyclovir and newer derivatives: Selective inhibition of herpes virus replication. Acyclovir conversion to nucleotide analog only in virus infected cells very little harm to uninfected cells! § AZT: reverse transcriptase inhibitor § Inhibitors of viral enzymes are used to treat influenza and HIV infection, e. g. : Protease inhibitors § -interferons inhibit spread of viruses to new cells Copyright © 2006 Pearson Education, Inc. , publishing as Benjamin Cummings Figure 20. 16 a

Protease Inhibitors HIV protease cleaves viral polypeptide into functional proteins Protease inhibition HIV cannot mature and noninfectious viruses are produced. Copyright © 2006 Pearson Education, Inc. , publishing as Benjamin Cummings

Antiprotozoan and Antihelminthic Drugs § Chloroquine, quinacrine, diiodohydroxyquin, pentamidine, and metronidazole (Flagyl) are used to treat protozoan infections. § Antihelminthic drugs include mebendazole, praziquantel, and ivermectin. Copyright © 2006 Pearson Education, Inc. , publishing as Benjamin Cummings

Antibiotic Assays to Guide Chemotherapy Two general methods for Susceptibility Testing: 1. Tube dilution method determines minimum inhibitory concentration (MIC) MIC = the lowest concentration of antibiotic sufficient to inhibit bacterial growth when tested in vitro. 2. Agar disk diffusion method determines susceptibility of an organism to a series of Kirby-Bauer test Copyright © 2006 Pearson Education, Inc. , publishing as Benjamin Cummings antibiotics.

Drug Resistance Penicillin G resistance of S. aureus from 3% to > 90% Multidrug-resistant S. aureus = MRSA or “superbug” Vancomycin-resistance Multi drug resistant TB = MDR-TB Mechanisms of resistance: § Vertical evolution due to spontaneous mutation § Horizontal evolution due to gene transfer Copyright © 2006 Pearson Education, Inc. , publishing as Benjamin Cummings