Introduction to antibiotics Flashcards
What is a key feature of the Beta-Lactam antibiotic structure?
The beta-lactam ring
This ring has to be intact in order for the drug to be active
Also has thiazolidine ring
How do beta-lactam antibiotics kill bacteria?
- As D-Ala-D-Ala analogs, they covalently bind to specific receptors (penicillin-binding proteins, aka PBPs)
- Act as competitive inhibitor to transpeptidase
- Also activate autolysins (bacterial enzymes that remodel/breadk down cell wall) –> Causes lesions in cell membrane and wall
- Thus inhibiting bacterial cell wall synthesis
What are the three main mechanisms microbes develop antibiotic resistance?
- ) Production of drug-inactivating enzymes
- ) Change structure of receptor or binding site (decrease affinity for the drug)
- ) Changes in drug permeation and transport (decreasing drug accumulation)
Bactericidal agents
Kills the bacteria
Bacteriostatic agents
Stop bacteria from reproducing while not necessarily killing them
Why can bacterial cells survive in water?
The bacterial cell wall prevents lysis from high osmotic pressure. If a human cell was placed in water the osmotic pressure would cause it to lyse.
Porin
Channels on proteins that are permeable to hydrophilic substances such as B-Lactams
What is peptidoglycan polymer chain?
The basic unit of the cell wall
What does the peptidoglycan polymer chain consist of?
Polysaccharides with alternating aminohexoses:
- N-acetylmuramic acid
- N-acetylglucosamine
What does the peptidoglycan polymer chain terminate in?
What is the relevance of this?
D-Alanine-D-Alanine + pentaglycine bridges
This is where cross-linking occurs, and B-lactams are structural analogs of the D-Ala-D-Ala substrate and therefore acts as competitive inhibitor
Transpeptidation in bacterial cell wall formation
A transpeptidase enzyme links the pentaglycine bridge of one peptidoglycan to the D-Ala-D-Ala of another forming the cross-link
What mechanisms can make a bacteria resistant to penicillin?
- ) Inactivation via plasmid-mediated B-lactamase (penicillinases) –> Most staphylococci and many gram (-) organisms
- ) Modification of PBPs to decrease affinity for drug –> MRSA, MRSE, and PRSP
- ) Impaired penetration to target PBPs (changes in porin structure in gram (-) rods)
- ) Presence of efflux pump
Cephalosporin main structure
B-lactam ring
Dihydrothiazine ring
Cephalosporin class
Class of B-lactam antibiotics
Cephalosporin mechanism of action
- Very similar to penicillin
- D-Ala-D-Ala analogs, bind to PBP, inhibit transpeptidase
- Activate autolysins
Monobactams
- Has monocyclic B-lactam ring (B-lactam class of Abxs)
- Drug name: Aztreonam
- Binds to a specific PBP (PBP3)
Carbapenems
- Synthetic B-lactam drugs structrually related to penicillins (B-lactam ring + 5-membered penem ring)
- Common drugs: Imipenem, Meropenem, Doripenem, and Ertapenem
- Resistant to most B-lactamases, but susceptible to metallo-B-Lactamase
B-lactamase inhibitors (basics)
- Resemble B-lactam drugs
- Inhibit B-lactamases by competitive inhibition
- Have low antibiotic activity when used alone
- Used with penicillins in fixed combinations
What are the main B-lactamase inhibitor/penicillin combinations?
- Timentin: Ticarcillin + Clavulanic acid
- Augmentin: Amoxicillin + Clavulanic acid
- Unasyn: Ampicillin + Sulbactam
- Zosyn: Piperacillin + Tazobactam
What class of antibiotics do penicillins and cephalosporins belong to?
B-Lactams
What penicillin drug and B-lactam inhibitor make up Augmentin?
Amoxicillin + Clavulanic acid
What penicillin drug and B-lactam inhibitor make up Unasyn?
Ampicillin + Sulbactam
What penicillin drug and B-lactam inhibitor make up Zosyn?
Piperacillin + Tazobactam
What penicillin drug and B-lactam inhibitor make up Timentin?
Ticarcillin + Clavulanic acid
Vancomycin
- No B-lactam ring (doesn’t bind to PBPs)
- NOT susceptible to B-lactamases
- Binds firmly to D-Ala-D-Ala terminus of peptidoglycan pentapeptide, thereby blocking the Transglycosylase Enzyme, thus blocking peptidoglycan elongation and cross-linking
- Also damages cytoplasmic membranes
Penicillin-Binding-Proteins (PBPs)
- Involved in final stages of peptidoglycan synthesis
- Are the target of beta-lactam antibiotics
- Belong to a group of enzymes called transpeptidases
What is the mechanism of Vancomycin resistance?
- Terminal D-Ala is replaced by D-lactate –> Decreases affinity of vancomycin
- Plasmid-mediated changes in permeability to the drug
What are come common Vancomycin-resistant bacteria?
- VRE: Vancomycin-resistant enterococci
- VRSA: Vancomycin-resistant staphylococcus aureus
Daptomycin
- Structure: novel cyclic lipopetide with spectrum similar to vancomycin
- Disrupts multiple aspects of bacterial cell membrane (creates holes that leak ions, causing depolarization)
Fosfomycin
- Antimetabolite inhibitor of cytosolic enolpyruvate transferase –> prevents the formation of N-acetylmuramic acid (precursor of peptidoglycan chain)
Cycloserine
An antimetabolite that blocks the incorporation of D-Ala into the pentapeptide side chain of the peptidoglycan
Bacitracin
A peptide antibiotic that interferes with a late stage in cell wall synthesis in gram (+) organisms
What is the mechanism of action of Ribosomal Antibiotics?
Inhibit protein synthesis by binding to and interfering with ribosomes
List of Ribosomal antibiotics
- Spectinomycin
- Macrolides
- Aminoglycosides
- Lincosamides
- Linezolid
- Chloramphenicol
- Tetracyclines
- Streptogramins
Bacterial ribosomes
- 70S –> 30S + 50S subunits
- Free in the cytoplasm
- Bind to mRNA
- Form polysomes (cluster of ribosomes held together by a strand of mRNA that each ribosome is translating)
- Display receptors for antibiotics on either subunit
Eukaryotic ribosomes structure and relevance to antibiotics
80S –> 40S + 60S subunits
Allows for antibiotics to be selective for bacterial ribosomes and not eukaryotic ribosomes; however, due to the simularities, ribosomal antibiotics have some degree of toxicitiy
Bacterial protein synthesis main steps
- ) Initiation (binds mRNA)
- ) Aminoacyl-tRNA binding (delivers AA)
- ) Transpeptidation by peptidyl transferase (growing peptide and new AA combined)
- ) Translocation (ribsome slides over on mRNA to next codon)
Which ribosomal antibiotics effect the 30S subunit?
What step of translation do they effect?
- Spectinomycin
- Aminoglycaosides
- Tetracyclines
I SAT on the small subunit
What ribosomal antibiotics effect the 50S subunit?
What step of translation do they each effect?
All of the ones that don’t effect the 30S
- Chloramphenicol
- Macrolides
- Lincosamides
- Streptogramins
- Linezolid
Spectinomycin
- Structure
- Bactericidal or Bacteriostatic?
- Which subunit does it bind?
- Mechanism of action?
- Aminocyclitol that is structurallly related to aminoglycosides
- Bacteriostatic
- Binds 30S subunit
- Inhibits formation of 70S initiation complex
Mechanism of Spectinomycin resistance
- Production of drug inactivating enzyme
- Alteration of specific receptor on 30S subunit
Aminoglycosides examples
- Neomycin
- Gentamicin
- Streptomycin
Aminoglycosides mechanism of action
- Binds to 30S subunit
- Blocks formation of 70S initiation complex
- Causes misreading of mRNA
- Prevent polysome formation, resulting in nonfunctional monosome
- Irreversibly inhibits protein synthesis –> bactericidal
Aminoglycosides mechanisms of resistance
- Produce (plasmid-mediated) drug-inactivating group transferases –> includes:
- Aminoglycoside acetyltransferase
- Aminoglycoside adenyltransferase
- Aminoglycoside phosphotransferase
- Alter 30S subunit (lowers affinity for Abx)
- Alter permeability
Tetracyclines mechanism of action
- Bind 30S subunit
- Inhibit binding of aminoacyl-tRNA to mRNA-ribosomal complex
- Bacteriostatic
Tetracycline mechanism of drug resistance
- Efflux of drugs by plasmid-coded efflux protein pump (Unique to Tetracyclines!)
- Altered permeability to drug
- Enzymatic inactivation of the drug
Chloramphenicol mechanism of action
- Binds 50S subunit
- Bacteriostatic
- Inhibits Peptidyl Transferase (in transpeptidation)
Chloramphenicol mechanism of drug resistance
- Produce (plasmid-coded) drug inactivating enzyme: Chloramphenicol Acetyltransferase
- Reduce permeability
Macrolides example
Erythromycin
Macrolides mechanism of action
- Bind 50S subunit
- Bacteriostatic
- Prevent the ribosome from translocation down the mRNA
Macrolides mechanism of drug resistance
- Methlyation of the receptor on the 50S subunit (plasmid-coded methylase) results in decreased affinity for the Abx
- Drug inactivating enzymes (esterases that hydrolyze macrolides)
- Reduced permeability to the drug
Lincosamides examples
- Lincomycin
- Clindamycin
Lincosamides mechanism of action
- Binds 50S subunit
- Prevent the ribosome from translocating down the mRNA
- Bacteriostatic
Lincosamide mechanism of drug resistance
- Methlation of the ribosomal receptor site
- Production of drug inactivating enzymes
- Reduced permeability to the drug
Streptogramins mechanism of action
- Binds to different sites on 50S ribosomal subunit
- Works syndergistically to prevent the ribosome from translocating down the mRNA
- For most susceptible organisms, they are bactericidal
Streptogramins mechanism of drug resistance
- Methylation of the quinupristin (S-type B) binding site
- Production of drug inactivating enzyme
- Active transport efflux
Streptogramins example
Synercid –> Composed of Streptogramins B & A (also known as quinupristin and dalfopristin)
MLS-type B resistance
- Macrolide-Lincosamide-Streptogramin-B resistance
- Methylase production confers resistance to the above antibiotics as they have the same ribosomal binding site
Linezolid mechanism of action
- Binds to unique site located on 23S rRNA of the 50S subunit
- Inhibit the formation of 70S ribosome (initiation complex)
- Also inhibits translocation of peptidyl-tRNA
Linezolid mechanism of drug resistance
- Mutation of the binding site on 23S rRNA (decreases affinity for Abx)
Sulfonamides and Trimethoprim drug class
Antifolate drugs (often used in combination with eachother)
Sulfonamides mechanism of action
- As antimetabolites of PABA (para-aminobenzoid acid) they are competitive inhibitors of DHPS (dihydrop’teroate synthase) in bacteria (competing with the PABA precursor)
Sulfonamides mechanism of resistance
- Decrease intracellular accumulation
- Increase in production of PABA
- Decrease in sensitivity of DHPS to the drugs
Trimethoprim mechanism of action
Act as a selective inhibitor of DHFR (dihydrofolate reductase)
Trimethoprim mechanism of resistance
Decrease in the sensitivity of DHFR to the Abx
Fluoroquinolones mechanism of action
- Inhibit prokaryotic topisomerase II (DNA Gyrase) and topiosomerase IV
- Bactericidal
Fluoroquinolones mechanism of resistance
- Decrease in intracellular accumulation (efflux pump or change in porin structure)
- Chromsome-encoded mutation in DNA gryase
- Plasmid-mediated resistance
Penicillins, Cephalosporins, Monobactams, and Carbapenems general mechanism of action
- Bind to PBPs as Ala-AAla analogs
- Inhibit transpeptidase
- Inhibit cross-linking of peptidoglycan polymers
- Activate autolysins
Penicillin, main mechanisms of resistance
- B-lactamases
- Modification of PBPs (Ex. MRSA/E and PRSP)
