Lectures 32-34 / Chapter 14

Paul Ehrlich

Found compound 606 and killed Treponema pallidum (syphillis)

Alexander Fleming

Discovered penicillin, the first natural antibiotic

Klarer, Mietzch, and Domagk

Discovered prontosil, which killed streptococcal and staphylococcal infections

What is the active breakdown product of prontosil?

Sulfanilamide

What was the first synthetic antimicrobial?

Sulfanilamide

Dorothy Hodgkin

Discovered the structure of penicillin using x-ray. Scientists could now modify semisynthetic penicillins

Chemotherapeutic agent

Any drug used to treat infection

Antibiotic

Usually targets one part of the bacteria (specific)

Example: a key bacterial enzyme is blocked

Antimicrobial

A broad term but can often mean multiple targets (broad)

Selective toxicity

Harms microbes but not damaging to the host

Chemotherapeutic index

Maximum tolerable dose per Kg of body weight

Minimum dose per Kg of body weight which cures the disease

Narrow spectrum

Targets only specific subsets of bacterial pathogens

Broad spectrum

Targets a wide variety of bacterial pathogens, including gram-positive and gram-negative species

What are 2 broad spectrum antibiotics?

Streptomycin and tetracycline

Broad spectrum disadvantage

The formation of superinfections

Superinfection

A secondary infection in a patient who already had an infection, associated with broad spectrum antibiotics

How does a superinfection form?

When you take broad spectrum antibiotics, it kills off healthy natural flora that keep opportunistic pathogens in check.

Bacteriostatic graph

Bacteriocidal graph

Bacteriolytic graph

Minimal inhibitory concentration (MIC)

The lowest concentration of the drug that will prevent the growth of an organism

Different tests for antiobioti activity

MIC test

Kirby-Bauer

E-test

Can the MIC test or the Kirby-Bauer test determine if a drug is bacteriocidal or bacteriostatic?

No

How to determine if a drug is bacteriocidal or bacteriostatic

Minimum bactericidal concentration (MBC)

Tube dilution test and removing the antibiotic

Minimum bactericidal concentration (MBC)

Tube dilution test and removing the antibiotic, if the cells grow in fresh medium without the antibiotic, the drug is… But if the cells do not grow, it is…

bacteriostatic

bactericidal

Attributes of an ideal antimicrobial

• Solubility in body fluids

• Selective toxicity

• Toxicity not easily altered

• Non-allergenic

• Stability

• Resistance by microorganisms not easily acquired

• Long shelf-life

• Reasonable cost

Dosage in children vs. adults

The amount of medication given during a certain time interval

In children: dosage is based upon the patients mass

In adults: standard dosage is used

Half-life of antibiotic

Rate at which 50% of a drug is eliminated from the plasma

Toxic dose

The maximum dose tolerated by the patient

Therapeutic dose

The minimum dose per kg of body weight that stops pathogen growth

The ratio of the therapeutic dose to the toxic dose is…

the chemotherapeutic index

Is the drug safe if it has a high or low chemotherapeutic index?

High

Which route of administration results in the highest amount of drug in the plasma?

IV (intravenous)

Synergistic drugs

Work poorly when they are given individually, but work very well when combined

Example: aminoglycoside and vancomycin

Antagonistic drugs

Mechanisms of action interfere with each other and diminish effectiveness

Example: penicillin and macrolides

Mechanisms of action for antibiotics: what can they target?

• Cell wall synthesis

• Cell membrane integrity

• DNA synthesis

• RNA synthesis

• Metabolism

Antibiotics that target the cell wall

• Beta-lactams

  • Penicillin

  • Cephalosporins

• Polypeptides

  • Vancomycin

  • Bacitracin

• Antimycobacterials

  • Isoniazid

  • Ethambutol

Penicillins

• Penicillin binds to the enzymes that attach NAM and NAG

• Without a cell wall, the growing cell bursts

Is penicillin bactericidal?

Yes

Is cephalosporin naturally occurring or synthetic?

Originally discovered in nature but has been modified, semisynthetic

Cephalosporin

Chemists have modified the basic structure of cephalosporin in ways that improve the drug’s effectiveness against penicillin resistant pathogens. New generations of the antibiotic

Polypeptide antibiotics that inhibit cell wall synthesis

Bacitracin and vancomycin

Bacitracin

• Topical application

• Against gram positives

Vancomycin

• Glycopeptide

• Important “last line” against antibiotic resistant S. aureus

Antimycobacterial antibiotics

Isoniazid and ethambutol

Isoniazid

Inhibits mycolic acid synthesis

Ethambutol

Inhibits incorporation of mycolic acid

How have microbes developed resistance to cell wall inhibiting antibiotics?

Bacteria with the enzyme beta-lactamase breaks a bond in the beta-lactam ring of penicillin to disable the molecule

Antibiotics that target the bacterial membrane

• Polymycin

• Tyrocidin

• Platansimycin

• Gramicidin

Polymycin B

• Targets lipid A, which only gram-negative bacteria have. Therefore its narrow spectrum

• Highly toxic

Gramicidin

• Cyclic peptide

• Inserts itself into the cytoplasmic membrane of gram-positive bacteria, disrupting the membrane and killing the cell

Antibiotics that affect DNA synthesis and integrity

• Metronidazole

• Sulfonamides

• Quinolones

Metronidazole

• Inactive until it enters anaerobic or microaerophilic bacterial cell

• Ferredoxin reduces metronidazole into active form

• Activates form binds to DNA and causes breaks

Sulfonamides

• Prevent the synthesis of folic acid, therefore inhibiting the production of nucleic acids

Folic acid is the precursor to nucleic acid

Why don’t sulfonamides harm humans?

Mammals do not synthesize folic acid, we have to get it from diet or microbes

Quinolones

• Inactivates DNA gyrase and topoisomerase

• Blocks progression of DNA replication fork

Why don’t quinolones harm humans?

Bacterial DNA gyrases are structurally distinct from mammal DNA gyrase

RNA synthesis inhibitor

Rifampin

Rifampin

Selectively binds to bacterial RNA polymerase and prevents transcription

What does rifampin treat?

Tuberculosis and meningococcal meningitis

Antibiotics that inhibit protein synthesis

• Aminoglycosides

• Tetracyclines

• Glycylcyclines

• Chloramphenicol

• Macrolides

• Lincosamides

• Oxazolidinones

• Streptogramins

Drugs that affect the 30S ribosomal subunit

• Aminoglycosides

• Tetracyclines

• Glycylcyclines

Aminoglyosides

Affects 30S ribosomal subunit*

Streptomycin, gentamicin, tobramycin

Causes misreading of mRNA

Tetracyclines

Affects 30S ribosomal subunit*

Doxycycline

Binds to 30S subunit and prevents tRNAs carrying amino acids from entering the A site

Glycylcyclines

Affects 30S ribosomal subunit*

Tigecycline FUNCTIONS IN TETRACYCLINE RESISTANT CELLS

Bind to 30S subunit and inhibit the entry of aminoacyl-tRNA into the A site.

Drugs that affect the 50S ribosomal subunit

• Chloramphenicol

• Macrolides

• Lincosamides

• Oxazolidinodes

• Streptogramins

Chloramphenicol

Affects 50S ribosomal subunit*

Prevents peptide bond formation by inhibiting peptidyltransferase

Macrolides

Affects 50S ribosomal subunit*

Erythromycin, azithromycin, clarithromycin

Bind to 50S subunit and inhibit translocation of tRNA from A to P sites

Lincosamides

Affects 50S ribosomal subunit*

Clindamycin

Bind to peptidyltransferase and prevents peptide bond formation

Oxazolidizones

Affects 50S ribosomal subunit*

Bind to 50S subunit and prevent 70S assembly

Streptogramins

Affects 50S ribosomal subunit*

Quinupristin, dalfopristin

Bind to 50S subunit and block tRNA from entry into A site, while blocking the exit of growing protein from the ribosome

Mechanisms of antimicrobial drug resistance by bacteria

• Drug modification or inactivation

• Blocked penetration

• Efflux pumps (altering porins in outer membrane)

• Target modification

• Target overproduction

• Enzymatic bypass

• Target mimicry

What does the influenza virus contain?

• Hemagglutinin

• Neuraminidase

Hemagglutinin function

Helps influenza virus bind to the host membrane receptors for entry by phagocytosis (helps virus get into cells)

Neuraminidase

Cleaves sialic acid to allow virus particles to escape from infected cells (helps virus exit cells to infect other cells)

Drugs that combat influenza

• Amantadine

• Oseltamivir (tamiflu)

• Zanamivir (relenza)

Treatments that inhibit HIV

• Protease inhibitors

• Entry inhibitors

• HIV treatment regimens

Protease inhibitors

Target the HIV protease enzyme

Entry inhibitors

Block the virus envelope protein from binding to the host receptor, so the virus never attaches

HIV treatment regimens

HAART (highly active antiretroviral therapy) involves administering combinations of three or more antiretroviral drugs

Antifugal agents

• Polyenes

• Azoles

• Allylamines

Antiprotozoan agents

• Metronidazole

• Quinine

• Chloroquinine

What drug is an antimalarial?

Chloroquinine

Antihelminthic drugs

• Niclosamide

• Praziquantel