Antimicrobial Drugs

The dawn of antibiotics

• Paul Erlich (1910)– Wanted to find the “magic bullet” for syphilis

– proposed the idea of the blood brain barrier

– Worked at staining tissues and first to come up with the idea behind “selective toxicity”

– Nobel Prize in 1908

Alexander Fleming

• A physician who studied bacterial action of blood and antisepsis

• Discovered and named Lysozyme

• Discovered mold growing on an agan plate(1928)

• 1945 Nobel Prize in Physiology or Medicine along with Chain and Florey

Chain and Florey

• 1940 developed a system for growing Penicillium and purifying the drug

• Tested the drug in mice, passed all trials

• Received the Nobel Prize in 1945 with Alexander Fleming for their work

Antibiotics

• A substance produced by a microorganism that inhibits or kills other microbes

Microbes that produce antibiotics

Range of activity

• Narrow range: target one group of microbes

• Broad range: target a wide group of different microbes

• Which one is the best?

Spectrum of activity

Targets of antimicrobial drugs

Targets of Cell Wall Synthesis

How does penicillin work?

• Inhibits formation of tetrapeptide side chains….which means….

• What happens if you put a cell in a solution with penicillin?

Some drugs target protein synthesis

Penicillin weakens the cell wall

Family tree of penicillins

Beta-lactam ring common with

penicillins and cephalosporins

How organisms degrade penicillins

Family of Penicillins

• Natural penicillins• Penicillinase-resistant penicillins

• Broad-spectrum penicillins• Extended-spectrum penicillins• Penicillins plus beta-lactamase inhibitors

Side chain varies for derivatives of penicillin

Cephalosporins

• Derived from fungus, Acremonium cephalosporium

• Chemical structure makes them resistant to beta-lactamase, low affinity for penicillin binding proteins

• Grouped into first, second, third, and fourth generation cephalosporins

Vancomycin

• Binds to the terminal amino acids of the peptide chain of NAM molecules, blocks peptidoglycan formation

Antibiotics that inhibit protein

synthesis

Aminoglycosides

• Bactericidal • Irreversibly bind to 30S ribosome, cause misreading of the mRNA

• Transported into cells that actively respire (not effective against ananerobes, streptococci, enterococci)

• Ex: streptomycin, gentamicin, tobramycin

Tetracyclines • Bind reversibly to 30S, block attachment of the tRNA to ribosome

• Actively transported into bacterial cells

• Effective against gram positive and gram negative

• Resistance: due to decrease in uptake or increase in excretion

• Ex: Doxycycline

Macrolides

• Reversibly bind to the 50S, prevent continuation of protein synthesis

• Drug of choice for patients allergic to penicillins

• Not good for Enterobacteriaceae• Ex: Erythromycin, Azithromycin• Resistance: enzymes that alter drug, decreased uptake

Oxazolidinones

• Reversibly bind to the 50S subunit, interfere with initiation of protein synthesis

• Used for treating gram positive infections resistant to Beta-lactam drugs and Vancomycin

• Ex: Linezolid

Antibiotics that inhibit nucleic acid

synthesis• Fluoroquinolones

– Inhibit topoisomerase

• Rifamycins– Blocks prokaryotic RNA polymerase from initiating transcription

Antibiotics that inhibit metabolic

pathways• Sulfonamides• Trimethoprims

Sulfanilamide is structurally similar

to PABA

Sulfonamides (sulfa drugs)

• First synthetic drugs to treat microbial infections

• Used to treat urinary tract infections (UTIs)

• Combination of trimethoprim and sulfamethoxazole (TMP-SMZ) example of synergism

Drugs used together inhibit folic acid

synthesis

Tests for microbial sensitivity

• Kirby-Bauer (disk diffusion method)– We did this in lab

• Determining the Minimum Inhibitory Concentration (MIC)

• E test– easier way to determine the MIC

Kirby-Bauer tests for sensitivity

Determining the Minimum Inhibitory Concentration (MIC)

E-test for MIC

What resistance looks like…

Mechanisms of Drug resistance

• Destruction or inactivation of the drug

• Prevention of penetration to target site

• Alteration of target site (mutation)

• Pumping of the drug out of the bacterial cell

Emerging Antibiotic Resistance

• Enterococci• Staphylococcus aureus• Steptococcus pneumoniae• Mycobacterium tuberculosis

Targets of Viral drugs