L2: Antimicrobial Agents Flashcards
Antibiotics and antimicrobial agents are different from disinfectants how?
They are specific for certain bacteria or microbes
Many antibiotics come from what?
What does this help explain?
Natural compounds made by bacteria or fungi to gain an evolutionary advantage in natural environments.
High resistance to some antibiotics since bacteria have been exposed to these compounds for millions of years
3 characteristics of the ideal antibiotic
- Target a variety of pathogens but spare normal flora
- Prohibit rapid development of resistance
- Selective for bacteria and does not damage host
What is the ideal antibiotic?
No such thing
Antibiotics are generally targeted against what?
Systems in all bacteria
The broader the spectrum of an antibiotics, the more likely what will happen?
The antibiotic will be more likely to attack normal flora
Do all antibiotics have resistance somewhere?
Yes
Limiting resistance to a drug has more to do with what? 2
- Prescribing practices of physicians
2. compliance of patients
Are all antibiotics toxic to the host?
Why or why not?
Yes
Since mitochondria are evolutionarily related to bacteria, many broad spectrum drugs affect mitochondria function
What are 4 of the main adverse effects of antibiotics?
- Allergic reactions (penicillin)
- Toxic (aplastic anemia, ototoxicity)
- Suppression of normal flora: (colon)
- Antimicrobial resistance
Antibiotics are split into what two categories?
- Bacteriostatic
2. Bactericidal
What is difference between bacteriostatic and bactericidal?
bacteriostatic = inhibit growth bacteriocidal = kill
Bacteriostatic drugs rely on what to eliminate pathogen?
Host immunity
Bactericidal drugs are useful when?
situations when host defenses cannot be relied upon to control the pathogen
What are the five main targets of an antibiotic?
- Cell wall
- protein synthesis
- nucleic acid synthesis
- metabolic pathways
- Cytoplasmic membrane
Which is the least toxic target of an antibiotic?
Why?
Cell wall
Mitochondria do not make peptidoglycan so it doesn’t attack them.
What is one side effect of a cell wall antibiotic?
Allergic reaction to peptidoglycan fragments
In terms of protein synthesis what is targeted in antibiotics? What will also be targeted?
Bacterial ribosomes
Mitochondrial ribosomes are inhibited leading to side effects
How useful are the antibiotics against nucleic acids?
Not very because there aren’t many conserved bacterial enzymes.
How useful are antibiotics against metabolic pathways?
Average, there are some unique bacterial metabolic enzymes
How are antibiotics used against cytoplasmic membranes?
WHy?
In a topical manner
Bacterial membranes are similar to eukaryotic membranes.
3 parts of cell wall synthesis?
- Cell wall subunits are made in cell cytoplasm
- Bactoprenol transports the subunits from inside the cell to ouside the cell
- Penicillin binding proteins link the subunits together into the existing cell wall
What anti-biotic attacks cytoplasmic synthesis of cell wall subunits?
Fosfomycin
Cycloserine
What anti-biotic attacks BACTOPRENOL and the transport of subunits?
Bacitracin
What do Beta-lactams do?
Attack PBP
What antibiotic is used against crosslinking?
Vancomycin
Beta-lactams contain a 4 membered ring called the what?
What does it mimic?
lactam ring
the terminal D-ala-D-ala of peptidoglycan side chains.
Where can beta-lactams bind?
transpeptidases and carboxypeptidases and inhibit their function.
Transpeptidases and carboxypeptidases are collectively known as what?
penicillin binding proteins or PBPs
inhibition of PBP inhibits what?
cross-linking of peptidoglycan chains weakening the mesh
What bacteria are not affected by Beta-lactams
Cell wall-free forms (e.g. Mycoplasmas and L-forms
Besides having a cell wall, what is the requirement for penicillin to inhibit a cell
Cells must be actively synthesizing cell walls
Natural penicillins have what spectrum?
What are they effective against? (2)
What are they sensitive to?
Narrow
Gram +
Gram - cocci
Acid
Penicillinase-resistant penicillin has side chains that prevent what?
inactivation from penicillinase enzymes
broad spectrum penicillins have what that give them their broad spectrum?
What are they effective against?
Modified side chains
Gram + and Gram -
Extended spectrum penicillins have greater effectiveness against what species of bacteria?
What else is it okay against?
Pseudomonas
Gram + organisms
Penicillin and Beta lactamase inhibitor are combination of what?
Penicillin drug and enzyme inhibitor
Augmentin is blend of what?
Amoxicillin + clavulanic acid
Tazoscin, Zosyn, Piprataz are what blended together?
Piperaccilin and tazobactam
In general, later generations of cephalosporins have greater effectiveness against what?
gram negative bacteria
Where has the basic structure of penicillin been modified? (2)
- Second ring structure
2. Altering R groups
What are the four goals of modifying Beta-lactams?
- Increase spectrum
- Increase stability in acid
- Bypass resistance mechanism
- Bypass allergic reactions
Why is it important to increase beta lactam acid stability?
Lactam ring is normally broken down by stomach acid so most penicillins must be administered parenterally
What percentage of the population is allergic to penicillin?
20%
What makes amoxicillin special?
Resistant to stomach acid
What makes clavulanic acid special?
Beta-lactamase inhibitor
amoxicillin + clavulanic acid = what?
Augmentin
What is the largest problem now in antibiotic resistance?
Extended spectrum Beta-lactamases
What are the three main ways beta-lactam is resisted?
Enzyme degradation
Reduced affinity PBP’s
Reduced membrane pemeability
Mutations to PBP genes result in what?
How does this happen?
Lower affinity of PBP’s for penicillin
- within the normal complement of PBPs in the cell
- the cell may acquire a low affinity PBP as an extra enzyme that can function when the antibiotic is present.
How does strep get reduced affinity PBP’s?
Mutation
How does MRSA get reduced affinity PBP’s?
Acquisition
How does reduced membrane permeability affect resistance to penicillin?
Loss of porins in the outer membrane of Gram-negative bacteria reduces the ability of penicillin to penetrate the cell
Penicillin is degraded by what enzyme?
Beta-lactamase
What inhibits beta-lactamase?
Clavulanic acid
Glycopeptides such as vancomycin inhibit what?
peptidoglycan cross-linking by binding to the terminal D-ala-D-ala of the peptide chain
Are glycopeptides effective against gram-negative bacteria?
No, because they cannot penetrate the outer membrane, too large to pass through the porins
Resistance to vancomycin is most commonly due to what?
substitution of the terminal D-ala with D-lac leading to loss of the central hydrogen bond with the amino group and a 1000-fold decrease in affinity
What is the relative size of vancomycin?
Huge
What exactly reduces vancomycin’s affinity with its target?
Change to oxgen in D-lac reduces affinity 1000x
Other cell wall antibiotics include?
Fosphomycin
Cycloserine
Bacitracin
Fosphomycin has what effect?
Blocks conversion of glucosamine to muramic acid
Cycloserine has what effect?
Acts as a D-alanine analog blocking incorporation
Bacitracin has what effect?
How is this primarily used?
Interferes with transfer of peptidoglycan precursors across the cell membrane.
Used primarily in topical ointments to inhibit Gram-positives
The majority of protein synthesis inhibitors bind to what?
Ribosomal RNA
What provides the selectivity of protein synthesis inhibitors?
Bacterial rRNA is different from eukaryotic rRNA
Drugs in the inhibition of protein synthesis group include? 7
Aminoglycosides Tetracyclins Macrolides Chloramphenicol Lincosamides Oxazolidinones Streptogramins
Aminoglycoside structure is what?
di, tri, and tetra-amine (amino) containing sugars (glycan
What is the mechanism of action of aminoglycosides?
In simple terms?
What does this cause?
Bind irreversibly to the 30S subunit of the bacterial ribosome and prevent binding of fmet-tRNA
(blocks initiation of translation and causes mis-reading of mRNA)
Cause codon misreading by 70S ribosomes
What are common aminoglycosides used? 5
Streptomycin gentamicin, tobramycin, amikacin netilimicin
Side effects of aminoglycosides? 2
Nephrotoxic
Ototoxic: damages the 8th cranial nerve required for inner ear function) causing nephrotoxic
Resistance mechanism to aminoglycosides mainly?
modification of the drug by specific enzymes such as acetylase, adenylase, and phosphorylase
Tetracycline structure?
planar molecules with 4 (tetra) six-member rings (cycline)
Mechanism of tetracycline action?
Is this binding irreversible?
What does that make tetracycline?
Binds reversibly to the 30S subunit and prevents binding of tRNAs to the acceptor site of the ribosome.
No, reversible
Bacteriostatic
Spectrum of tetracyclin?
Very broad
Common tetracyclines in use? (4)
Doxycycline
Minocycline
oxytetracycline
Chlortetracycline
Resistance mechanism to tetracyclines?
efflux, the ability to pump the antibiotic back out of the cell after it has entered
Side effects of tetracyclines? (2)
- Broad spectrum leads to suppression of natural intestinal flora causing stomach upset and diarrhea
- Interference with bone development and permanent staining of teeth in children
What population should not get tetracycline?
Children under 8 years of age
Structure of chloramphenicol?
modified nitrobenzene ring
Mechanism of chloramphenicol?
Does it bind irreversibly?
What does that make this?
Binds to the peptidyl transferase center of 23S rRNA in the 50S subunit inhibiting peptide bond formation
No
Bacteriostatic
Resistance mechanism to chloramphenicol? (3)
- Mainly enzymatic modification of the drug by acetylation at the OH group by enzyme CAT.
- Target modification
- Change in permeability
Side effects of chloramphenicol? 2
- bone marrow suppressant
2. Irreversible aplastic anemia
Macrolides, Lincosamides, and Streptogramins (MLS) have what mechanism of action?
bind to the same region of the 23S rRNA preventing translocation or some other aspect of translation. (prevent continuation of protein synthesis)
MLS has what for resistance?
target modification by methylation of a specific nucleotide of the 23S rRNA
Side effects of MLS? 1
Clindamycin severely alters the balance of natural flora in the intestines and is not effective against C dif allowing it to flourish and cause pseudomembranous colitis
Examples of MLS antibiotics?
- Erythromycin
- Azithromycin (Z-pak)
- Clindamycin
- Synercid (quinupristin/dalfopristin)
Osazolidinones have what method of action? (2)
- target 23S rRNA
2. prevent joining of the 50S to the 30S subunit of the ribosome
Oxazolidinones are used for what type of infections?
multi-resistant Gram-positive infections
Example of oxazolidinone?
Linezolid (Zyvox)
Fusidic acid has what mechanism of action?
What is it used most for?
Inhibits the function of EF-G
used primarily for Staph infections
Nucleic acid synthesis inhibitors drugs include? (5)
- Quinolones
- Rifampicin
- Sulfonamides
- Trimethoprim
- Metronidazole (Flagyl)
Quinolones include what four drugs?
1st generation: Nalidixic acid
2nd generation: Fluorquinolone/Ciprofloxacin
3rd generation: Levofloxacin
4th generation: Gemifloxacin
Is the structure of quinolones natural or synthesis?
Synthetic
Mechanism of quinolone action? 2
- Interferes with the function of the two bacterial type II topoisomerases, gyrase and topoisomerase IV
- Traps the DNA-enzyme complex in the cleaved state
Quinolone action is similar to what?
anticancer drugs that inhibit human type II topoisomerase
Quinolone resistance is because of what?
Chromosomal mutations in a highly conserved region of all topoisomerases that lower affinity for the drug
Mutations that make bacterial enzymes resistance to bacterial topoisomerase inhibitors actually has what other effect?
make them sensitive to eukaryotic inhibitors
Quinolone is not recommended for who? (2)
Why?
children or lactating women
because of possible effects on cartilage development
Rifampicin has what mechanism of action?
Blocks the initiation of transcription by binding selectively to bacterial RNA polymerase.
Rifampicin is used primarily for what infection?
Mycobacterial infections (TB).
Rifampcin resistance is due to what?
Chromosomal mutations in the target
Side effects of rifampicin? (2)
Rash
Jaundice
What are the two inhibitors of folic acid synthesis that also inhibit bacterial nucleic acid synthesis?
- sulfonamides
2. trimethoprim
Structure of sulfonamides
Synthetic analogs of PABA
Sulfonamides have what mechanism of action?
Interferes with the synthesis of nucleic acid bases (purines and pyrimidines) by competing with PABA in the first step on the pathway to synthesis of folic acid.
Selectivity of sulfonamides against bacteria and not host is because of what?
the fact that humans do not synthesize folic acid but require it as a nutrient
Sulfonamides are used to treat what?
Urinary tract infections
How is resistance acquired in sulfonamides?
Acquisition of a second enzyme with lower affinity for the drug
Side effects of sulfonamides? 2
- rashes
2. bone marrow suppression
Trimethoprim has what for structure?
Analog of the aminohydroxypyrimidine moiety of folic acid
Mechanism of trimethoprim action?
Inhibition of folic acid synthesis at a later stage by inhibition of dihydrofolate reductase
What gives trimethoprim its selectivity despite dihydrofolate reductase being in all mammalian cells?
trimethoprim has a higher affinity for the bacterial version
what is trimethoprim frequently given in addition to?
For what infections?
sulfamethoxazole
urinary tract
Resistance to trimethoprim is done how?
Acquisition of a second DHFR enzyme with lower affinity for the drug
Side effects to trimethoprim are worse in what patients?
in AIDS patients
Mechanism of action of metronidazole/flagyl?
What must happen first?
Results in DNA breaks
Pro-drug must be reduced to active drug within the bacterial cell
Flagyl/metronidazole is only effective on what?
anaerobic bacteria because only they can supply the necessary reducing environment
Resistance to metronidazole/flagyl is due to what? (2)
decreased uptake or decreased reduction
Side effects of metronidazole/flagyl?
Rare CNS effects
What is the reducing agent of metronidazole?
Ferredoxin
Antibiotics against the plasma membrane include? 2
- polymixins
2. daptomycin (cubicin)
Structure of polymixins?
large cyclic polypeptides
Mechanism of polymixin action?
How is it used?
disrupt bacterial membranes
topically
Resistance to polymixins is due to what?
reduced uptake
Daptomycin/Cubicin has what structure?
lipopeptide
Daptomycin/Cubicin has what mechanism of action?
Inserts into bacterial membrane by lipid portion and disrupts membrane potential which stops everything else
Use of Daptomycin/Cubicin is when? (3)
to severe skin infections,
bacteremia
endocarditis caused by multiply resistant Gram-positive organisms.
Side effects of Daptomycin/Cubicin 2
Renal impairment,
effects on skeletal muscle
Is there resistance to Daptomycin/Cubicin
Yes but not defined
Mycobacteria are tough to make drugs for because of what? (4)
- the waxy outer layer prevents penetration of many antibiotics
- they are frequently intracellular
- they grow extremely slowly requiring long term treatment
- common in immuno-compromised patients
Treatment for mycobacteria typically involves what?
cocktail of drugs including rifampicin, streptomycin, isoniazid, ethambutol, and pyrazinamide
What is a problem with cocktail mycobacterial treatment?
Compliance
Mechanism of isoniazid?
What does it require first?
Prevents mycolic acid synthesis
conversion to active form by catalase function so catalase mutants are resistant to the drug.
Mechanism of ethambutol?
Resistance occurs when?
Side effect?
Inhibits synthesis of arabinoglycans
if it is not part of a cocktail
optic neuritis.
Pyrazinamide has what structure?
A nicotinamide analog
Dapsone is what type of molecule?
What is it used for?
sulfonamide
M. leprae infections
5 mechanisms of antibiotic resistance?
- Enzymatic modification of the antibiotic.
- Modification of target
- Decreased permeability
- Loss of transport system
- Reverse transport out of cell
Acquisition of resistance can be due to what? (2)
Which is major cause?
- Spontaneous mutation
2. Acquisition of new genes: Major
What is the alteration of existing genes called?
Vertical evolution
Acquisition of new genes for resistance is called what?
Horizontal transfer
Resistance plasmids are transmitted between who? (2)
- same bacterial species
2. different bacterial species
What is wrong with antibiotics right now?
- We have made two new ones since the 1960’s.
- Bacteria are so good at evolving resistance
- Bacteria can share resistance
- No incentives for pharm companies to make new antibiotics
Based on the current state of antibiotics, what is it important for us physicians to know?
What we’ve got is probably what we’ll have for the foreseeable future, so it is incumbent upon physicians to prescribe them wisely to retain their effectiveness as long as possible.
