Lecture 6: Antimicrobial Compounds and Resistance Mechanisms Flashcards
Bactericidal
“cidal” - kills susceptible bacteria - host responses not needed
Bacteriostatic
“static” inhibits bacterial growth and relies on host defences to clear the bacteria
Narrow spectrum antibiotics
active against a small group of bacteria (good)
Broad spectrum antibiotics
Active against a much wider variety of bacteria (bad)
Resistance
When an organism no longer responds to a therapy OR is associated with failure in vivo
Sensitive
When an organism responds to an antimicrobial and has activity in vivo
Antimicrobial Targets
Cell Wall Synthesis
- Beta Lactams: Penicillins, cephalosporins, carbapenems, monobactams
- Vancomycin Bacitracin
- Cell Membrane: Polymyxins
Nucleic Acid Synthesis
- Folate synthesis: Sulfonamides; Trimethoprim
- DNA Gyrase: Quinolones
- RNA Polymerase: Rifampin
Protein Synthesis
- 50S subunit: macrolides, clindamycin, linezolid, chloramphenicol, streptogramins
- 30S subunit: Tetracyclines, Aminoglycosides
Cell Wall Synthesis Inhibitors Beta-Lactam antibiotics
- The beta-lactam ring is the central component of all beta-lactam antibiotics
Antibiotic in this class include: Penicillins, Amoxicillin, Cephalosporins, Minocyclines, and Carbapenems - They work by inhibiting cell wall synthesis
Cell wall components and Beta-lactam antibiotics
- The transpeptidase enzyme crosslinks the peptidoglycan
- Beta lactams interfere with binding
- Cell wall stays permeable, then bacteria dies
- Beta-lactam antibiotics bind to transpeptidase enzymee complex and blocks this reaction
Most common Penicillins
- PenicillinG
- PenicillinV
- Cloxaclillin
- Amoxicillin
- Piperacillin
- Most specific, focus on certain parts
Common Cephalosporins
1. 1st Gen
2. 2nd Gen
3. 3rd Gen
- Ampicillin
- Cefazolin
- Ceftazidime, Ceftriaxone, Cefixime
Common Carbapenems
- Ertapenem
- Meropenem
*Best and most broad, most activity, last line of drugs
Beta-lactam Antibiotics
- Active in both gram positive and gram negatives
- Penicillin and ampicillin are narrow spectrum
- 1st gen cephalosporins are narrow spectrum. 3rd and 4th generation of cephalosporins have broader coverage and usually used for more resistant organisms
- Carbapenems are very broad spectrum antibiotics and used as antibiotics of last resort (BROADEST)
Glycopeptides: Non Beta-Lactam Cell wall active agents
- Glycopeptides act on the cell wall of GRAM POSITIVE organisms
- Stops the extension of the peptidoglycan unit of the bacterial cell wall
- Drugs in this class include: Vancomycin and Teicoplanin
Protein Synthesis Inhibitors
- Binds parts of the ribosomes
- Ribosomes in bacteria are structures that make proteins from nucleic acids
- Ribosomes have subunits called 30S and 50S (70S ribosome in prokaryotic cells)
- Antibiotics bind the 30S and 50S subunit of ribosomes and stop protein synthesis in bacteria
Protein Synthesis Inhibitor Famalies
- Tetracyclines (block the attachment of tRNA to the ribosome - important)
Ex: Demeclocycline - Macrolides (prevent the continuation of protein synthesis - important)
Ex: Azithromycin - good for pneumonia - Chloramphenicol (prevents peptide bonds from being formed - less important than the other two)
Nucleic Acid Inhibitors: Fluoroquinolones
- Stop protein synthesis by messing with nucleic acid
- Prevents DNA RNA replication by targeting
Prevents DNA gyrase or RNA topoisomerase
Fluoroquinolones
- Excellent drugs with a broad spectrum of activity
- Good tissue penetration
Example: Moxifloxacin
Metabolic Inhibitors
- Trimethoprim/Sulfamethoxazole (Septra, Bactrim)
- Inhibitors of the active form of folic acid (tetrahydrofolic acid)
- Trimethoprim - structural analogue of DHF (Dihydrofolic acid) and competitive inhibitor of dihydrofolate reductase
- Sulfamethoxazole - structural analogue of PABA and competitively inhibits synthesis of DHF
Intrinsic Resistance
You don’t have to do anything for it (Like how your skin is waterproof)
Acquired Resistance
- Developed and got from other things (“Like a jacket” to keep you warm, can be shared, but have to go get it)
Testing for resistance
We won’t test, we’ll analyze results
We care about you acquired because you want to control the spread
- Antibiotic testing is done in vitro (in glass)
- Data will show what will be effective or ineffective
- The interpretations of the testing are reported as either Sensitive (S): patient will get better, Intermediate (I): up the antibiotic dose, or Resistant (R): patient will not get better
- If organism grows in presence of antibiotics - then R, if organism doesn’t grow then S
Microbroth Dilution
- The last well before growth is seen is the Minimum Inhibitory Concentration (MIC)
- Take concentration of bug and drug, where the lack of growth is the concentration that is MIC
- Different concentrations of antibiotics from L of the plate to the R
- Suspension of bacteria added to the plate and incubated
Bacterial Resistance Characteristics
- Inherited or acquired
- The generation of mutation(s) is partly because of the short replication times - some bacterial generations are as short as 20 min
- Frequency of mutations is about 1 in 10 million cells
- A colony of bacteria has 100 million cells - potential for up to 10 mutation events in one colony
4 Resistance Mechanisms + what is a resistance mechanism
- Resistance genes can be on the bacterial chromosome (intrinsic) or on a motile gene element called a plasmid (circular strand of DNA)
1. Efflux pump - bug pumps out antibiotics, reduced permeability, changes thickness and size
2. Reduced permeability
3. Enzymatic inactivation - bacteria makes enzyme that breaks down
4. Altered binding site - antibiotic binds to site, if site is altered it will not bind
(1 and 2 resistance mechanism can’t be passed on, 3 and 4 is the one to be nervous about because it means limiting options for patient
Bacterial Resistance
- Resistant mechanisms often have a resistance mechanism often have a costs associated to them (Fitness or metabolic)
- 2 types of resistant mechanisms - either “always on” (usually acquired) or “inducible” (intrinsic - following antibiotic exposure)
- Lack of selective pressure will result in the loss of a particular resistance mechanism (particularly the acquired resistance phenotype)
- There are several ways that resistance mechanisms may be shared in inter or intra species (FINISHED AT SLIDE 23)
