Lecture 19, 10/26 (Maybruck 4): Chemotheraputic Drugs

Audio for lecture on 10/26 available here.

• • Slide 1 Antimicrobial target: nucleic acids(handout from 10/4)
• o naladixic acid – inhibits function of DNA gyrase. DNA gyrase unwinds DNA and allows for efficient storage of the chromosome. It also allows for DNA synthesis ot occur
• • slide 2 Antimicrobial target: Protein synthesis
• o protein synthesis involves four primary parts: two ribosomal subunits (50s and 30s → unique to prokaryotes), tRNA and mRNA.
• o Aminoglycosides – attach to 30s ribosomal subunit which causes the tRNA to misread the mRNA. In turn the protein is incorrectly formed and is nonfunctioning.
• o Tetracycline – attaches to 50s ribosomal subunit and prevents tRNA from binding to that sight. (tRNA is bringing amino acids over to ribosomal subunit to create a protein). Considered a semisynthetic drug.
• o Chloramphenicol – prevents bonding of amino acids together. Prevents peptide bond.
• o erithromyacin – binds to 50s portion of subunit and prevents mRNA from sliding through the ribosome. This is where tRNA reads the mRNA and figures out what to bind where and form protein. Because mRNA can’t slide through – protein isn’t made.
• o NOTE: Cells need to be metabolically active in order for the above antibiotics to function
• • Slide 3 Antimicrobial target: Cell membrane
• o These two drugs can work on a cell that is not metabolically active.
• o Polymyxin (broad spectrum) – targets cell membrane. Acts as a surfactant, integrates into cell → disrupts it → cell dies.
• o Chloroquine – little bit more selective then polymyxin. An anti-malarial drug. The causative agent of malaria is the protozoan plasmodium.
• • Life cycle of plasmodium – mosquitoe → to human → to liver → attack red blood cells. Plasmodium brings nutrients (hemoglobin) into food vacuole.
• • Uses enzymes to break down majority of hemoglobin. Doesn’t like the iron cofactor “heme”. Instead it converts iron into hemozoin (Hz). Chloroquine inturupts this function. Plasmodium will be unable to detoxify “heme” and the cell becomes toxified.
• • Slide 4 Antimicrobial target: Folic acid synthesis
• o Folic acid synthesis is unique to bacteria and protozoans.
• o Folic acid is a precursor of DNA RNA and proteins. We get our folic acid from food we consume. Bacteria and protozoans make it for themselves.
• o We prevent folic acid synthesis in a bacteria/protozoans with competitive inhibition of an enzyme.
• o 2 examples:
• • Hexokinase enzyme is responsible for taking glucose, binding it to phosphate and forms glucose 6 phosphate → initial reaction in glycolysis. Take an enzyme that is similar to glucose and present it in a greater concentration. This will take the place of the actual glucose and in turn prevent the process from occurring.
• • Folic acid synthesis forms a dihydroteric acid (which is only formed using Para-aminobenzoic acid (PABA)). PABA binds to pteridine synthetase and forms precurusor to folic acid. We create a “pseudo”PABA that outcompetes the actual PABA. Drugs used are sulfonomides and trimethoprim.
• • Slide 5 antibacterial drug groups: penicillin and related
• o Penicillin (penicillium chrysogenum) – prevents synthesis of the peptidoglycan cell wall.
• o Semi–synthetic antibiotic: what we would be prescribed. It is the modified version of the real thing. Causes it to become broad spectrum
• o Alpha – hemolyses: when bacteria reduces iron or the “heme” group. Cause pnemonia
• o Beta – hemolyses: involved in rupturing red blood cells. Cause strep throat.
• • Slide 6
• o Cephalosporin – Cephalosporium acremonium (similar to penicillin but induces fewer allergic reactions) – removes enteric bacteria (bacteria that colonize intestines) Ex. E. coli.
• o Salmonella is another example → prevents water absorption.
• • Slide 7 animoglycoside tetracycline, and chlorampheniccol
• o See slide 2
• • Antimicrobial Chemotherapy part II
• • Slide 1
• o Fungi are eukaryotic making their removal “tricky” because their functions at a molecular level are similar to ours.
• o Target ergosterol which is in the cell membrane of fungi cells. Ergosterol is similar to cholesterol. Function of ergosterol is to support the cell.
• o Macrolide polyene antibiotics target the ergosterol.
• o It is used to attack Histoplasmosis (fungal infection that causes respiratory problems)
• o Griseofulvin – targets cyctoskeleton of fungi cells. In particular it attacks the microtubules. This keeps the cell from forming properly. Drug is used to treat fungi infections in the hair skin or nails.
• • Slide 2
• o Azoles – prevents ergosterol synthesis. Fights off Cryptococcus meningitis. Meningitis affects the meninges in the spine.
• o Flucytosine
• • Fungi use this flucytosine analog to build the DNA strand. This in turn prevents DNA synthesis.
• • Used to combat candidal cystits (a yeast infection associated with bladder)
• Slide 3 drugs specific to the removal of protozoans
• o Metronidazole – removes anaerobic microorganisms
• • Upon administration to the individual the drug becomes inactive – a prodrug. In turn the protozoans injest this and then it become active in the protozoans. Once in the protozoan it interferes with DNA structure.
• o Entomeaba histolytica amoeba - Fecal contamination is a source of this protozoa. Protozoan in the cyst form is resistant to stomach acid. It then progresses to the large intestine and turns into trophozoite form. In this form it inhibits water absorbtion by the large intestine.