MOA Flashcards
Aminoglycoside (AG) Examples
gentamycin
tobramycin
amikacin
streptomycin
plazomycin (new)
AG MOA (General)
multifactorial: inhibition of protein synthesis
Aminoglycosides irreversibly bind to the 30S ribosomal subunit (some to 50S subunits), which results in a disruption in the initiation of protein synthesis, a measurable decrease in protein synthesis, and misreading of messenger RNA.
AG MOA for gram negative bacteria
- For Gram-negative bacteria, the aminoglycosides must first bind to and diffuse through the outer membrane through porin proteins.
- Once in the periplasmic space, the aminoglycosides must then be transported across the cytoplasmic (inner) membrane a process that is dependent upon a membrane potential, is energy-dependent, requires oxygen (why they are not useful against anaerobes), and is rate-limiting.
- Following transport across the cytoplasmic membrane, the aminoglycosides bind to polysomes and inhibit the synthesis of proteins, which disrupts the structure of the cytoplasmic membrane.
AGs: Bactericidal or bacteriostatic
bactericidal in a concentration-dependent manner
but
bacteriostatic against enterococcus
Cephalosporin Examples
1st: cefazolin, cephalexin
2nd: cefuroxime, cefotetan, cefprozil, cefoxitin
3rd: ceftriaxone, cefoperazone, ceftazidime, cefpodoxime
4th: cefepime
4th?: ceftaroline
Cephalosporin MOA (General)
Interfere with cell wall synthesis by binding to and inhibiting enzymes, called penicillin-binding proteins (PBPs i.e. responsible for peptidoglycan cross-linking)
Inhibition of PBPs by beta-lactam antibiotics leads to inhibition of the final transpeptidation step of peptidoglycan synthesis –> exposing a less osmotically-stable cell wall that leads to decreased bacterial growth, bacterial cell lysis, and death.
Cephalosporin: Bactericidal or bacteriostatic
bactericidal in a time-dependent manner
FQ Examples
Ciprofloxacin, levofloxacin, moxifloxacin, delafloxacin
FQ MOA (General)
Unique mechanism of action that includes inhibition of DNA synthesis by binding to and inhibiting bacterial topoisomerases (enzymes needed for maintaining cellular DNA in an appropriate state of supercoiling in both the replicating and nonreplicating regions of the bacterial chromosome)
FQ MOA (Specific)
Inhibition of DNA gyrase prevents the relaxation of positively supercoiled DNA that is required for normal transcription and replication.
FQs form a stable complex with DNA and DNA gyrase, which blocks the replicating fork leading to a sudden and lethal cessation of DNA replication (For many Gram-negative bacteria, DNA gyrase is the primary target of the FQs)
Inhibition of topoisomerase IV interferes with the separation of replicated chromosomal DNA into respective daughter cells during cell division that are the product of DNA replication, causing a cessation in DNA replication (For many Gram-positive bacteria (S. aureus), topoisomerase IV is the primary target of the FQs)
FQ: Bactericidal or bacteriostatic
concentration-dependent bactericidal activity
Macrolide Examples
Erythromycin, azithromycin, clarithromycin
Macrolide MOA
Macrolide antibiotics interfere with microbial protein synthesis (translocation steps) at the ribosomal level. The macrolides reversibly bind to the 50S ribosomal subunit to induce dissociation of peptidyl transfer RNA from the ribosome during the elongation phase so that protein synthesis is suppressed and bacterial growth is inhibited.
Macrolide: Bactericidal or bacteriostatic
Bacteriostatic activity
HOWEVER
They may display bactericidal activity when present at high concentrations against very susceptible organisms (Streptococcus pneumoniae, Streptococcus pyogenes)
Tetracycline Examples
tetracycline, doxycycline, minocycline
Tetracycline and tetracycline analogs MOA
Inhibit bacterial protein synthesis by reversibly binding to the 30S ribosome, blocking binding of amino-acyl tRNA to the acceptor (A) site on the mRNA-ribosomal complex.
This prevents the addition of amino acid residues to the elongating peptide chain and inhibits protein synthesis
Tetracyclines: Bactericidal or bacteriostatic
bacteriostatic in action
BUT
May be bactericidal in high concentrations or against highly susceptible organisms
TMP and SMX Examples
TMP = Trimethoprim
SMX = Sulfamethoxazole
TMP and SMX MOA (Both General)
Produce sequential blockade of microbial folic acid synthesis
SMX MOA
A sulfonamide that competitively inhibits the incorporation of p-aminobenzoic acid (PABA) into folic acid by inhibiting dihydropteroate synthetase, which inhibits the formation of dihydrofolic acid
TMP MOA
Competitively inhibits the activity of bacterial dihydrofolate reductase to prevent the reduction of dihydrofolate to tetrahydrofolate
SMX + TMP: Bactericidal or bacteriostatic
Together, these two agents produce sequential inhibition of the synthesis of folate, which is necessary for microbial production of DNA, producing a synergistic bactericidal effect against many Gram-positive and Gram-negative aerobic bacteria that may not be present with each agent alone
Penicillin Examples (All)
Natural Penicillins: Aqueous Penicillin G, Benzathine Penicillin, Procaine Penicillin G, Penicillin VK
Penicillinase-Resistant Penicillins: Nafcillin, Oxacillin, Methicillin, Dicloxacillin
Aminopenicillins: Ampicillin, Amoxicillin
Carboxypenicillins: Ticarcillin
Ureidopenicillins: Piperacillin
β-Lactamase Inhibitor Combinations: Ampicillin-Sulbactam (Unasyn), Amoxicillin-Clavulanate (Augmentin), Ticarcillin-Clavulanate (Timentin), Piperacillin-Tazobactam (Zosyn)
Beta-LACTAMS (Penicillins, Cephalosporins, Carbapenems, Monobactams) General MOA
ALL SAME: Inhibitors of cell wall synthesis
Beta lactams MOA (Specific)
Penicillins interfere with bacterial cell wall synthesis by binding to and inhibiting enzymes, called penicillin-binding proteins (PBPs expressed during cell division)
Inhibition of PBPs by beta-lactam antibiotics leads to inhibition of the final transpeptidation step of peptidoglycan synthesis, exposing a less osmotically-stable cell membrane that leads to decreased bacterial growth, bacterial cell lysis, and death.
Beta lactams: Bactericidal or bacteriostatic
bactericidal, except against Enterococcus spp. where they display bacteriostatic activity
Glycopeptide Example
Vancomycin
Streptogramin Example
Quinupristin-dalfopristin (Synercid®)
Oxazolidinones Example
Linezolid (Zyvox®), Tedizolid (Sivextro™)
Lipopeptides Example
Daptomycin (Cubicin®)
Lipoglycopeptides Examples
Telavancin (Vibativ™), Dalbavancin (Dalvance™), Oritavancin (Orbactiv™)
Vanc (glycopeptide) MOA
Inhibits the synthesis of the bacterial cell wall by blocking glycopeptide polymerization at a site different from that of the beta-lactams.
Vancomycin inhibits synthesis and assembly during the second stage of cell wall synthesis by firmly binding to the D-alanyl-D-alanine portion of cell wall precursors. Vancomycin prevents cross-linking and further elongation of peptidoglycan, which weakens the cell wall making it susceptible to lysis.
Vanc: Bactericidal or bacteriostatic
slowly bactericidal in a time-dependent (?) manner, except against Enterococcus spp. where it displays bacteriostatic activity
QUINUPRISTIN / DALFOPRISTIN (Synercid) MOA
Quinupristin and dalfopristin act individually on the 50S ribosomal subunit to inhibit early and late stages of bacterial protein synthesis
QUINUPRISTIN / DALFOPRISTIN (Synercid): Bactericidal or bacteriostatic
each agent alone is bacteriostatic, but the combination produces an additive or synergistic effect (sometimes bactericidal)
OXAZOLIDINONES MOA
Oxazolidinones bind to the 50S ribosomal subunit near the surface interface of the 30S subunit, producing inhibition of the 70S initiation complex for protein synthesis (ultimately, inhibits protein synthesis).
Unique: Cross-resistance with other protein synthesis inhibitors unlikely.
OXAZOLIDINONES: Bactericidal or bacteriostatic
For the most part, oxazolidinones are bacteriostatic
LIPOPEPTIDES MOA
Daptomycin binds to bacterial membranes and inserts its lipophilic tail into the cell wall to form a transmembrane channel –> leakage of cellular contents and rapid depolarization of the membrane potential leading to inhibition of protein, DNA, and RNA synthesis, resulting in bacterial cell death.
LIPOPEPTIDES: Bactericidal or bacteriostatic
Daptomycin exhibits rapid, concentration-dependent bactericidal activity.
LIPOGLYCOPEPTIDES MOA
All lipoglycopeptides interfere with the polymerization and cross-linking of peptidoglycan by binding to the D-Ala-D-Ala terminus. The lipid side chain anchors the drugs to the cell membrane and concentrates the drug at the site of action.
Oritavancin and telavancin (NOT dalbavancin) also appear to bind to bacterial membranes and insert their lipophilic tails into the cell wall to form a transmembrane channel (like daptomycin) –> causes leakage of cellular contents and rapid depolarization of the membrane potential leading to inhibition of protein, DNA, and RNA synthesis, resulting in bacterial cell death.
Polymyxin Examples
polymyxin B and colistin
Polymyxin MOA
Polymyxins are cationic detergents that bind to the anionic lipopolysaccharide molecules of the outer cell membrane of Gram-negative bacteria causing displacement of calcium and magnesium, which normally stabilizes the cell membrane. This action leads to changes in cell wall permeability, leakage of cellular contents, and subsequent cell death.
Polymyxin: Bactericidal or bacteriostatic
concentration-dependent bactericidal activity
