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
Range of activity
• Narrow range: target one group of microbes
• Broad range: target a wide group of different microbes
• Which one is the best?
How does penicillin work?
• Inhibits formation of tetrapeptide side chains….which means….
• What happens if you put a cell in a solution with penicillin?
Family of Penicillins
• Natural penicillins• Penicillinase-resistant penicillins
• Broad-spectrum penicillins• Extended-spectrum penicillins• Penicillins plus beta-lactamase inhibitors
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
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
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
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
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