What is chemotherapy?
Treatment of disease by means of chemicals (drugs) that have a specific toxic effect upon disease producing microorganisms, or that selectively destroy cancer tissue
Selective toxicity (avoid killing wrong cells) Mechanisms of resistance (strategies that foreign cells use to survive)
What is cidal vs static pathways to overcome an infection with drug therapy?
Bactericidal- Kill the big directly
Bacteriostatic- stop the bug from replicating; let the host immune system do the work
What are the mechanisms of antibiotics?
Damaging the cell wall/membrane- cell wall synthesis inhibitors, drugs that damage cell membranes
Inhibitors of protein synthesis- ribosomal inhibitors
Inhibitors of RNA- RNA polymerase inhibitors
Inhibitors of DNA- DNA gyrase inhibitors, inhibitors of purine synthesis, inflict DNA damage
What are cell walls synthesis inhibitors?
Inhibit synthesis of peptidoglycan cell wall of bacteria, makes it have leaks
Cell wall synthesis is ongoing as bacteria divide all the time so it’s easy target
Cell walls much easier to access in gram positive cells (main target)
Can target gram negative through porins
What are the 5 classes of cell wall synthesis inhibitors?
What are the mechanisms of resistance of bacteria?
Some bacteria produce enzymes that break down the chemical structure of certain drugs
(Beta lactamase resistance)
Can protect against resistance by protecting beta lactam ring by using larger molecules with chemical groups that block beta lactamases (cloxacillin)
What is MRSA?
Methicillin resistant staph aureus
Example if antibiotic resistance
Methicillin is an antibiotic that is used for in vitro sensitivity testing
Methicillin is quite toxic to humans but is a penicillin
What are the side effects of beta lactams?
Tend to be well tolerated
Good selective toxicity
Covers early generation gram + and late generation broad spectrum
Beta lactamase producing organisms provide resistance
Counter this with decoy (amoxicillin + clavulanate)
How do glycopeptides work?
Glycopeptides (GP) inhibit polymerization of peptidoglycan (PG) chains
PG polymers are called NAM-NAG
They target the easier gram + membranes
Transglycosylase removes a lipid carrier from an incoming NAM-NAG, this allows the incoming NAM-NAG to join the PG polymer
GP bind ti D-ALA-D-ALA terminus preventing transglycosylase step
Without this step incoming NAG-NAM can’t join PG polymer
What are polymyoxins?
Bind to lipopolysaccharide (LPS) a d phospholipids in the cell membrane
Damages cell membrane, interferes with cell functions and may cause lysis
Side effects- lacks selective toxicity so they are toxic (so they are used topically)
What are ribosomal inhibitors?
Bind either 50S or 30S subunit if ribosome
Half protein synthesis
Selectively toxic because difference in structure of ribosomes between human and bacteria cells
What are all the types of ribosomal inhibitors?
Inhibitors of 30S:
Inhibitors of 50S:
What are fluoroquinolones?
DNA gyrase and topoisomerase IV are essential for efficient DNA replication
DNA gyrase relaxes positively supercoiled DNA
Topoisomerase IV separates DNA strands after replication
Selectively toxic because of the structural differences between human and bacterial DNA gyrase
Poor safety record- CNS (dizziness), rash (photosensitivity), arrhythmia (QT long), tendinipathy
What are purine synthesis inhibitors?
DNA is comprised of purines and pyrimidines
Folate (tetrahydrofolate THF) is necessary precursor
Bacteria must synthesize THF
Drugs inhibit enzymes that synthesize THF
Humans acquire folate from diet so it’s selectively toxic
What is synergy?
2 drugs inhibit enzymes along the same biochemical pathway
Ex: trimethoprim + sulfamethoxazole
What are nitrofurans?
What is metronidazole?
Nitrofurans- acted upon by bacterial enzymes to form a reactive intermediate
Metronidazole- similar mechanism to nitrofurantoin
Acted upon by bacterial enzyme to form reactive intermediate
Activated by anaerobic bacteria
What pharmokinetic property would a drug need in order to cross into the CNS?
In order to cross into CNS, drugs must be lipophilic
Necessary to treat CNS infections such as meningitis
What pharmacokinetic property would you look for in a drug to treat a patient with a urinary tract infection (UTI)?
In order to treat UTI, it is important to use a drug that concentrates in the kidney
Therefore the drug must be in its active form when it reaches the kidney
Drugs that are eliminated by the kidney are likely to be more effective for UTI
What types of mechanisms of resistance would you expect with:
Mechanisms of resistance:
Enzyme inhibitors- create more enzyme, change shape of enzyme
Ribosomal inhibitors- alter shape of binding site
Intracellular drugs- prevent entry into the cell, pump drug out of cell
What is pan drug resistance (PDR)?
Bacteria that confer resistance to the last resort antibiotic (colistin)
Colistin resistance genes have been isolated, therefore bacteria now have the ability to pass mechanisms of resistance to other bacteria
Slides 13-15 antibiotics 2
Who discovered penicillin and how?
Sir Alexander Fleming
Worked in bacteria lab and returned from vacation to find dish with staphylococcus had mold on it and the area around the mold was clear of staph (mold was killing staph)
Slides 16-18 antibiotics 2
What is tuberculosis (TB) and mycobacterium?
TB is one of leading causes of death globally
Has ability to remain hidden and dormant for long periods of time
When active it can be deadly, most commonly affects lungs
TB is caused by mycobacteria (similar but not identical to gram +/- bacteria)
Slides 21-27 antibiotics 2
How do you treat mycobacteria?
Similarities to bacteria, so uses similar drugs
RNA polymerase inhibitors
Protein synthesis inhibitors
Putin’s synthesis inhibitors
However there are also some grits used specifically for TB:
Mycolic acid synthesis inhibitors
Slides 23-27 antibiotics 2