Chemotherapeutic Agents
Antibiotics
- A chemical substance naturally produced by microorganism that has the capacity to inhibit or kill other microbes
Vancomycin
- Disrupts peptidoglycan (NAM) a.Gram positive bacteria b.Used to treat serious systemic infections c.Resistance - VRE and VRSA
Narrow spectrum
- Drugs that work against only a few kinds of pathogens. Example - penicillin is limited for treatment of Gram positive infection
Broad spectrum
- Effective against many different types of microorganisms. Example - erythromycin can be be used to treat Gram positive, Gram negative, chlamidial and rickettsial infections.
Penicillin family
- drugs that inhibit peptidoglycan synthesis by preventing the crosslinking of the NAM subunits. The penicillin binds to and deactivates the enzyme that catalyzes the NAM crosslinking. Without the ability to form peptidoglycan, the cell wall weakens and ultimately the cell lyses. The active portion of these drugs are referred to as the beta lactam rings a.Natural penicillins- Penicillin G (Discovered by Fleming in 1929) and Penicillin V b.Semisynthetic penicillins- Methicillin, Ampicillin and Amoxicillin c.β Lactam ring Structure - structure in the penicillin that is required for function d.Resistance due to presence of Beta-lactamase, modification of the bacterial enzyme so that the drug no longer binds, or a change in the bacterial outer membrane to prevent entrance of the drug.
Cephalosporins
- have a similar action to the penicillin family. They possess the beta lactam ring structure and disrupt the formation of the peptidoglycan by blocking the crosslinking of NAM. a.Spectrum - Gram positive, later generations are active against Gram negatives b.Natural - Cephalothin c.Semisynthetic - Ceflacor and Cephalexin d.Resistance would be similar to penicillin family
Azoles
- interfere with sterol synthesis; plasma membrane synthesis a. Ketoconazole - topical use for skin; oral use for systemic infections b. Itraconazole and Fluconazole - interferes with ergosterol synthesis c. Clotrimazole and Miconazole - topical use for skin and mucous membrane
Antimetabolites
- the drug mimics a growth factor; pathogen erroneously binds to the analog
Selective toxicity
- want to select a drug that will have maximum activity against the pathogen with minimal damage to host
Antibacterial Drugs that disrupt protein synthesis
1. Aminoglycosides 2. Tetracycline 3. Chloramphenicol 4. Macrolides
Chemotherapeutic Agents
1. Antibiotics 2. Synthetic Drug
Mechanisms of action
1. Inhibition of cell wall synthesis 2. Disruption of nucleic acid synthesis 3. Inhibition of protein synthesis 4. Disrupt cell membrane function 5. Antimetabolites
Spectrum of Activity
1. Narrow spectrum 2. Broad spectrum 3. Selective toxicity 4. Adverse effects 5. Mechanisms of drug resistance
Antibacterial Drugs that disrupt cell wall synthesis
1. Penicillin family 2. Cephalosporins 3. Bacitracin 4. Vancomycin
Anti-viral drug Targets
1. Viral Uncoating 2. Base analogs 3. Reverse transcriptase inhibitors 4. Protease inhibitors 5. Neuraminidase inhibitors
Sulfonamides
A synthetic drug that is a growth analog of PABA. It binds irreversibly to the enzyme that produces folic acid; inhibit folic acid synthesis b. Broad spectrum. c. Adverse effects are rare but include allergic reactions, anemia, jaundice and mental retardation of fetus in the last trimester of pregnancy. d. Competitive inhibition - competes with PABA for enzyme active site
Aminoglycosides
Aminoglycosides - This group of drugs target the 30S ribosomal subunit by changing its shape. This makes it impossible for the ribosomes to read the mRNA correctly, disrupting protein synthesis. d.Broad spectrum of activity. e.Kanamycin, streptomycin, gentamycin, neomycin and tobramycin. f.Toxicity - adverse effects include toxicity to kidneys and auditory nerves. g.Resistance - Aerobic bacteria alter pores to prevent uptake of drug or synthesize enzymes that break down the drug. Anaerobic bacteria are naturally resistant.
Bacitracin
Appears to have three modes of action - interferes with cell wall synthesis, inhibits RNA transcription and damages cell membrane. a.Narrow spectrum - Gram +. b.Topical use only - toxic to kidneys. c.Resistance due to changes in the cell membrane that block entrance of the drug
Polymyxin B
Destroys cell membranes. e. Spectrum -effective against Gram - bacteria, particularly Pseudomonas f. Topical use only due to kidney toxicity g. Resistance due to changes in the cell membranes that prohibit entrance of the drug.
Nucleic acid synthesis
Flucocytosine - inhibits RNA and DNA synthesis; systemic fungal infections
Cell Division
Griseofulvin - inhibition of mitotic microtubules; infections of skin
Quinolones
Inhibit topoisomerases, enzymes required for nucleic acid synthesis a.Spectrum - Gram negatives and Gram positives b. Ciproflaxacin and ofloxacin
Antifungal Drug Targets
Plasma membrane 1. Macrolide polyenes 2. Azoles
Antibacterial Drugs that Disrupt Cell Membranes
Polymyxin B
Antibacterial Drugs that disrupt nucleic acid synthesis
Quinolones
Antibacterial Drugs that disrupt folate biosynthesis
Sulfonamides
Tetracycline
Tetracycline- This group of drugs prevents the tRNA molecules from binding to the 30S ribosomal subunit during protein synthesis, disrupting protein synthesis. a. Broad spectrum of activity, most effective against Gram + and - bacteria. b.Tetracycline, Doxycycline, and Trimocycline. c. Adverse effects include diarrhea, nausea, sensitivity to light, complexes with calcium and discolors teeth as well as affects bone strength. d. Resistance due to alteration of pores to prevent drug entrance, alter binding site on ribosome to allow tRNA binding with drug present, or actively pump drug out (Efflux)
Adverse effects
a. Allergic reaction b. Toxic effects c. Suppression of normal flora
Mechanisms of drug resistance
a. Plasmids b. Contributing factors
Inhibition of protein synthesis
accomplish this by binding to the ribosome complex and preventing translation; one issue with toxicity is that mitochondrial ribosomes have same structure as prokaryotic ribosomes
Chloramphenicol
binds to the 50S ribosomal subunit and prevents protein synthesis by blocking movement along the mRNA. a.Broad spectrum b.Toxicity- rarely used due to adverse effect; patient may suffer from aplastic anemia or neurological damage c.Resistance due to R - plasmid gene that codes for an enzyme that deactivates the drug.
Macrolides
binds to the 50S ribosomal subunit, blocking protein synthesis by preventing elongation. a. Spectrum -effective against Gram + and a few gram b. Erythromycin, Clarithromycin, and Azithromycin c. Adverse effects include nausea, mild gastrointestinal pain and vomiting d. Resistance due to changes in the bacterial ribosomal RNA that prevents the drug from binding or R plasmid genes that code for macrolide digesting enzymes.
Inhibition of cell wall synthesis
disrupt peptidoglycan synthesis; can prevent assembly or peptide bridge formation
Macrolide polyenes
inhibit protein synthesis a. Amphotericin B - used to treat systemic fungal infections; injury to plasma membrane b. Nystatin - toxic for systemic use
Disrupt cell membrane function
may interact with phospholipids in membrane or complex sterols
Synthetic Drug
synthesized; can me a modified natural antibiotic (semi-synthetic)
Disruption of nucleic acid synthesis
various mechanisms; base analogs are erroneously incorporated into nucleic acids; may interfere with replication process
