Chapter 9 - Antimicrobial Therapy

antibiotics

microbial products or their derivatives (natural products) that kill susceptible microbes or inhibit their growth

Paul Ehrlich

Who developed the concept of selective toxicity?

compound 606 (Salvarson)

an arsenic compound that was believed to effectively treat syphilis in the 1900s

Sahachiro Hata

Who developed the compound 606 (Salvarson)?

Ernest Duchesne

Who was penicillin first discovered by?

tuberculosis

Streptomycin is an antibiotic effective against…

Selman Waksman

Who was streptomycin discovered by?

mid 1940s to early 1950s

Most antibiotic discoveries occurred in what time period?

selective toxicity

ability of drug to kill or inhibit pathogen while damaging host as little as possible

therapeutic dose

drug level required for clinical treatment of a infection

toxic dose

drug level at which drug becomes too toxic for patient

therapeutic index

ratio of toxic dose to therapeutic dose

larger

The _____ the therapeutic index, the better the drug

side effects

undesirable effects of drugs on host cells

narrow-spectrum drugs

drugs effective against a limited range of microorganisms

broad-spectrum drugs

drugs effective against a large range of microorganisms

minimal inhibitory concentration (MIC)

lowest concentration of drug that inhibits the growth of a pathogen

minimal lethal concentration (MLC)

lowest concentration of drug that kills a pathogen

1. inhibitors of cell wall synthesis

2. protein synthesis inhibitors

3. metabolic antagonists

4. nucleic acid synthesis inhibition

4 main modes of action of antibiotics

β-lactam ring

Most crucial feature of the cillin drugs is the…

inhibits peptidoglycan synthesis within the cell wall

What does the β-lactam ring do in cillin drugs?

β-lactamase (pencillinase)

Penicillin resistant organisms produce what enzyme?

blocks the enzyme that catalyzes transpeptidation which prevents the synthesis of complete cell walls leading to lysis of the cell

Cillin drugs mode of action

transpeptidation

process of the formation of cross-links in peptidoglycan

log phase

Cillin drugs act on bacteria in what phase?

penicillin G

penicillin V

2 naturally occurring penicillins

~1-5%

About what percent of adults in the U.S. are allergic to penicillin?

Cephalosporins

Broad-spectrum antibiotic that is structurally & functionally similar to penicillins

generations

groups of drugs, sequentially developed, with different antimicrobial spectra

First generation = gram-positive

Second generation = gram-positive, more gram-negative

Third generation = gram-negative, some have less gram-positive

Four generation = gram-positive, gram-negative (broad-spectrum)

Describe the 4 generations of cephalosporins

1. vancomycin

2. teicoplanin

2 glycopeptide antibiotics that inhibit cell wall synthesis

inhibits cell wall synthesis by binding to terminal peptides D-Ala-D-Ala

Vancomycin & Teicoplanin mode of action

vancomycin

drug important in treatment of antibiotic-resistant staphylococcal & enterococcal infections

A site

ribosomal site where new tRNAs bind onto the codon to bring in new amino acids

P site

ribosomal site where the growing polypeptide chain occurs

E site

ribosomal site where used up tRNAs leave from

1. mRNA reading

2. aminoacyl-tRNA binding

3. translocation

4. peptide bond formation

4 steps of peptide synthesis in bacteria

30S

aminoglycoside antibiotics bind to what ribosomal subunit?

interfere with protein synthesis by directly inhibiting the process & causing misreading of the mRNA

aminoglycoside antibiotics mode of action

30S

Tetracyclines bind to what ribosomal subunit?

bacteriostatic

Are tetracyclines cidal or static? Against what microorganisms?

inhibits binding of aminoacyl-tRNA molecules to the A site of the ribosome

Tetracyclines mode of action

50S (23S rRNA)

Macrolides bind to what ribosomal subunit?

bacteriostatic

Are macrolides cidal or static? Against what microorganisms?

macrolides

Drug used when patients are allergic to penicillin

inhibits translocation & peptide chain elongation

Macrolides mode of action

erythromycin

Example of macrolide drug

50S (23S rRNA)

Chloramphenicol binds to what ribosomal subunit?

inhibits peptidyl transferase reaction

Chloramphenicol mode of action

structural analogs

molecules that are structurally similar to, and compete with, naturally occurring metabolic intermediates

p-aminobenzoic acid (PABA)

Sulfonamides/Sulfa drugs are analogs of…

metabolic antagonist (analog of PABA - inhibition of folic acid synthesis enzymes)

Sulfonamides/Sulfa drugs mode of action

metabolic antagonist (interferes with folic acid production)

Trimethoprim mode of action

nalidixic acid

Quinolones were first synthesized from…

inhibit bacterial DNA-gyrase & topoisomerase II that disrupts DNA replication & repair

Quinolones mode of action

bactericidal

Are quinolones cidal or static? Against what microorganisms?

ergosterol

Fungal cell membranes require ____ which is not found in human membranes

bind directly to ergosterol to inhibit cell membrane formation of fungi

Polyenes antifungal mode of action

1. Amphotericin B

2. Nystatin

2 examples of polyenes antifungals

Nystatin

antifungal used to control superficial Candida infections

block last step of ergosterol biosynthesis to inhibit cell membrane formation

Azoles antifungal mode of infection

1. ketoconazole

2. fluconazole

2 examples of azoles antifungals

ketoconazole

antifungal treats superficial mycoses of skin & mucous membranes

fluconazole

antifungal treats candidiasis, cryptococcal, & coccidioidal meningitis; used prophylactically in AIDS patients

Griseofulvin

antifungal made by Penicillium given orally for chronic superficial mycoses

impairs mitotic spindle formation & cell division

Griseofulvin antifungal mode of infection

uracil

5-flucytosine is an analog of…

interferes with RNA synthesis (analog to uracil)

5-flucytosine antifungal mode of action

dCTP

Cidofovir is an analog to…

inhibits viral DNA polymerase (analog to dCTP)

Cidofovir antiviral mode of action

guanosine

Acyclovir is an analog to…

inhibits herpes virus DNA polymerase (analog to guanosine)

Acyclovir antiviral mode of action

nucleoside

adenine arabinoside (vidarabine) is a _____ analog

inhibits herpes virus enzymes involved in DNA synthesis

adenine arabinoside (vidarabine) antiviral mode of action

inhibits herpes virus DNA polymerase

Foscarnet antiviral mode of action

1. acyclovir

2. adenine arabinoside (vidarabine)

3. foscarnet

3 antiviral drugs for herpesvirus infections

1. amantidine

2. tamiflu

2 antiviral drugs for influenza

blocks penetration & uncoating of influenza virus

Amantidine antiviral mode of action

neuraminidase inhibitor

Tamiflu antiviral mode of action

1. reverse transcriptase (RT) inhibitors

2. protease inhibitors

3. integrase inhibitors

4. fusion inhibitors

4 types of anti-HIV drugs

prevent HIV entry into cells

fusion inhibitor anti-HIV drug mode of action

prevent incorporation of HIV genome into host chromosome

integrase inhibitor anti-HIV drug mode of action

mimic peptide bond that is normally attacked by the protease

protease inhibitor anti-HIV drug mode of action

inhibits apicoplast of some protozoa

Clindamycin mode of action when used as an antiprotozoal drug

inhibits folic acid synthesis

Trimethoprim-sulfamethoxazole mode of action when used as an antiprotozoal drug

antibiotics

What can be used to treat protozoan diseases?

chloroquine

antiprotozoan drug that can treat malaria caused by any of the five Plasmodium spp.

prevents hemozoin formation that results in lysis of the parasite and red blood cell

Chloroquine mode of action when used as an antiprotozoal drug

1. atovaquone

2. pyrimethamine

2 drugs used to Plasmodium & Toxoplasma gondii

inhibits cytochrome bc₁ complex of the electron transport chain, blocking ATP synthesis

Atovaquone mode of action when used as an antiprotozoal drug

inhibits folic acid synthesis by blocking the dihydrofolate reductase enzyme

Pyrimethamine mode of action when used as an antiprotozoal drug

1. inactivation of drug by enzymes

2. modified drug target

3. modified cell wall proteins

4. activation of drug efflux pumps

4 mechanisms of drug resistance