Mechanisms of action of antibiotics Flashcards
Pharmacokinetics
All the ways that the body manipulates a drug including absorption, distribution, metabolism, and excretion
Pharmacodynamics
Describes the biochemical and physiologic effects of the drug and its mechanism of action on the bacteria
Bacteriostatic
Antimicrobial agents that inhibit growth and/or reproduction of the infecting agent, but fail to actually kill the agent
Bacteriocidal
Antimicrobial agents that are capable of causing irreversible damage or death to the organism (eg B-lactams)
Five main mechanisms by which antibiotics inhibit or kill bacteria
- Interference with cell wall synthesis (most common)
- Interference with protein synthesis (second most common)
- Interference with cytoplasmic membrane function
- Interference with nucleic acid synthesis
- Interference with metabolic pathway
Bacteria that inhibit cell wall synthesis
- Beta lactams (penicillins, cephalosporins, carbapenems, monobactams)
- Vancomysin
- Bacitracin
Inhibition of cell wall synthesis general
-Interfere with peptidoglycan synthesis and murein assembly
Beta-Lactam antibiotics inhibition of cell wall synthesis mechanism
Binds at active site of transpeptidase enzyme that cross-links the peptidoglycan strands by mimicking the D-alanyl-D-alanine residues that would normally bind
-Irreversible, bacteriocidal
Four main B-lactam classes
- Penicillins
- Cephalosporins
- Monobactams
- Carbapenems
Penicillins
- Different classes
- Natural (penicillin G and penicillin)
- Penicillinase-resistant penicillins (methicillin, nafcillin, isoxazolyl penicillins)
- Aminopenicillins (ampicillin, amoxicillin)
- Carboxypenicillins (carbenicillin, ticarcillin)
- Acyl ureidopenicillins (azlocillin, mezlocillin, piperacillin)
Cephalosporins
- Categorized by generations
- Each generation exhibits increased spectrum of activity as well as increased resistance to destruction by B-lactamase enzymes
Monobactams
Active against aerobic gram-negative bacilli
Aztreonam
Carbapenems
Active against essentially all pathogenic organisms and resistance to destruction by the extended spectrum B-lactamses
Glycopeptides
Fosfomycin
MIC
minimal inhibitory concentration - represents the lowest concentration of the antibiotic which prevents the organisms from multiplying - not necessarily killing the organism.
MBC
minimal bacteriocidal concentration - represents the lowest concentration which kills the organism - not relevant with bacteriostatic agents.
Antibiotics that interfere with nucleic acid synthesis
- Folate synthesis (sulfonamides, trimethoprim)
- DNA gyrase (quinolones)
- RNA polymerase (Rifampin)
Antibiotics that interfere with protein synthesis
50s subunit & 30s subunit
Three potential mechanisms of protein synthesis inhibition
- Interfere with formation of the 30s initiation complex
- Interfere with formation of the 70s ribosome by the 30s initiation complex and 50s ribosome
- Block elongation process of assembling amino acids into a polypeptide
Aminoglycosides
- Gentamycin, tobramycin, amikacin, streptomycin
- Interference with the initiation of protein synthesis by binding to the 30s ribosome and changing its shape so that it inhibits protein synthesis by causing a misreading of messenger RNA information
- Bacteriocidal
Linezolid
- Block formation if the translocation initiation complex by binding to the 23s portion of the 50s subunit
- Bacteriostatic
Macrolids
- Erythromycin, azithromycin, clarithromycin
- Act by binding to the 23S rRNA molecule (in the 50s subunit) of the bacterial ribosome blocking the exit of the growing polypeptide
- Bacteriostatic
Lincosamides
- Clindamycin
- Similar action as the macrolids–works primarily by binding to the 50s ribosomal subunit of bacteria. Clindamycin disrupts protein synthesis by interfering with the transpeptidation reaction, where thereby inhibits early chain elongation
- Bacteriostatic
Chloramphenicol
- Binds to residues in the 23s rRNA of the 50s ribosomal subunit preventing peptide bond formation (substrate binding). Many genera of gram-positive and gram-negative bacteria and several anaerobes such as Bacteroides fragilis, as well as Rickettsia and chlamydia spp are susceptible.
- Efficacy against salmonella
- Can produce bone marrow suppression
- Bacteriostatic
Tetracyclines
- Tetracycline, minocycline, doxycycline, demeclocycline, tigecycline
- Inhibit bacterial protein synthesis by blocking the attachment of the transfer RNA-amino acid to the ribosome 30s subunit.
- Inhibitors of the codon-anticodon interaction. Capable of inhibiting protein synthesis in both 70s and 80s ribosomes but preferentially bind to bacterial ribosomes due to structural differences in RNA subunits
- Bacteriostatic
Bacteria that interfere with cytoplasmic membrane function
- Polymyxins (topical): cationic detergent-like activity
- Bacitracin (topical): disrupt cytoplasmic membranes
- Anti-fungals: Polyenes (eg amphotericin), Azoles (eg fluconazole), Allyamines (eg terbinafine)–alteration of sterol (ergosterol) structure and function
Quinolones/Fluorquinolones
- Ciprofloxacin, levofloxacin, norfloxacin
- Inhibit DNA gyrases or topoisomerases required for supercoiling of DNA
- Bacteriocidal
Metronidazole
- Metabolic cytotoxic byproducts disrupt DNA
- Bacteriocidal
Rifampin
- Binds to DNA-dependent RNA polymerase inhibiting initiation of RNA synthesis
- Bacteriocidal
Bacitracin
- Topical
- Inhibits RNA transcription
- Bacteriocidal
Nucleoside analogs
Acyclovir (viruses), Zidovudine (retroviruses)
Sulfonamides and Dapsone
- Sulfonamides–bacteriostatic
- Dapsone–Bacteriocidal
- Compete with p-aminobenzoic acid (PABA) preventing synthesis of folic acid.
Trimethoprim
- Inhibit dihydrofolate reductase preventing synthesis of folic acid
- Bacteriostatic
Trimethoprim and sulfamethoxazole
- Use in combination (Bactrim ratio 1:5) is often used as the two drugs are synergistic in activity making the combination bacteriocidal rather than bacteriostatic
- Treat infections like UTI, otitis media, bronchitis, traveler’s diarrhea, and shigellosis (bacillary dysentery)
Lipoglycopeptides (Telavancin)
Activity against vancomycin strains, Rx gram positive complicated skin and soft tissue infections
Cyclic lipopeptides (Daptomycin)
- Rx gram positive infections including MRSA
- Binds to bacterial membrane and causes rapid depolarization of the cell membrane; the loss of membrane potential leads to inhibition of DNA, RNA and protein synthesis.
Glycylcyclines (Tigecycline)
- Rx gram positive (MRSA), gram negatives
- Similar mechanism of action as tetracycline antibiotics
Oxazolidinones (Linezolid)
- Rx MRSA and VRE (vancomysin resistant enterococcus)
- Inhibits microbial protein synthesis (50s)
Penicillin binding proteins
- Set of transpeptidases that catalyze the final cross-linking reactions of peptidoglycan synthesis.
- The high MW PBP’s are involved in different activities during peptidoglycan synthesis, whereas, the low PBP’s function as D-alanine carboxypeptidases. (e.g. PBP2)
How do the B-Lactams work?
- PBPs bind to the terminal D-alanyl-D-alanine residues of peptidoglycan precursors to catalyze transpeptidation
- β-lactam antibiotics bind to PBPs because they are structurally analogous to D-Ala-D-Ala.
- When antibiotic binds to the PBP, the β-lactam amide bond is ruptured to form a covalent bond with the catalytic serine residue at the PBPs active site.
- Irreversible
