Glycopeptides(Vancomycin)

• Mechanism of Action 
• Effectiveness 
• Mechanism of Resistance 

Mechanism of action: Vancomycin binds to D-ala-D-ala at the end of peptide side chain in peptidoglycan precursors, blocking PBPs from catalyzing transglycosylation/transpeptidation steps of peptidoglycan synthesis. 

EFFECTIVE ON GRAM + not Gram - bacteria due to the permeability barrier of Gram-negative outter membrane. (too large to fit through aquaporin) Used for beta lactam resistant infections, ex. MRSA or in pts with a beta lactam hypersensitivity. 

Mechanism of Resistance: bacteria acquire genes encoding machinery to produce an altered peptidoglycan structure that lacks D ala-D-ala groups (switches to D ala-D-lac), so vancomycin is unable to bind efficiently. This resistance is often associated with enterococci in hospitals (VRE). Genes of resistance usually transferred via plasmids or transposons. 

Cycloserine 

• Mechanism of action 

Inhibits peptidoglycan crosslinking, structurally similar to D-alanine and used as a second line TB therapy

Mechanism of Action- Competitive inhibitor in two sequential reactions: 

1) in Alanine racemase (conversion of L--> D ala) 

2) D-alanyl-D-alanine synthase (inhibition of D-ala-D-ala linkage) 

Acts as a competitive inhibitor with a higher affinity for enzyme than natural substrate, D-alanine

Bacitracin 

• Mechanism of Action 

PEPTIDE ANTIBIOTIC TOO TOXIC FOR SYSTEMIC USE (ingestion or IV)

Mechanism of action- Binds to pyrophosphate on the lipid carrier for peptidoglycan precursors (bactoprenol-P) and blocks its recycling. Without this lipid carrier, peptidoglycan synthesis cannot continue. 

Group A Streptococci are 10x more sensitive than other bacteria. Bacitracin "A-disks" are a diagnostic for Group A Strep (GAS) 

Daptomycin (Lipopeptide) 

• Mechanism of Action 

Bactericidal, narrow spectrum (Gram positive bacteria) 

Mechanism of action- Binds to and disrupts the cytoplasmic membrane possibly via loss of membrane potential. Confers activity against antibiotic-resistant bacteria. 

Polymyxin (Lipopeptide antibiotic) 

• Mechanism of action 

Bactericidal, narrow spectrum (Gram neg. bacteria. Has adverse effects due to toxicity limit use to infection caused by antibiotic resistant bacteria or topical use. 

Mechanism of action-Binds to LPS in Gram (-) bacteria leading to disruption of the outer membrane and cytoplasmic membrane, novel mechanism confers activity against antibiotic-resistant Gram negative bacteria. 

Tetracyclines

• Method of Action
• Adverse Effects 
• Resistance Mechanisms

Broad spectrum and bacteriostatic

Mechanism of Action- Binds to 30S ribosomal subunit and interferes with the binding of aminoacyl tRNA to the ribosome. 

Adverse Effects: Upset stomach and teeth stains in kids. 

There are derivatives that exist that differ at chemical substituents at R positions, these alter pharmacologically, but not the mechanism of action. 

Resistance: 1)**Tetracycline resistance pump**(most important)

2)Mutations on the ribosome (tetracycline not allowed to bind to 30S subunit) 

Over the years, tetracycline has lost its effectiveness due to overuse and widespread resistance. 

Aminoglycosides (ex. gentamicin, amikacin, kanamycin, tobramycin)

• Mechanism of Action 
• Toxicity
• Mechanism of Resistance

Bactericidal and Broad Spectrum 

Mechanism of Action- Binds irreversibly to 30s ribosomal subunit and causes misreading(incorporation of the wrong aa into growing protein) and premature release of the mRNA. 

Useful for Gram (-) but doesn't penetrate Gram (+) well

Toxicity: Ototoxic and Nephrotoxic

Mechanism of Resistance: Enzymatic mod. of the antibiotic to prevent aminoglycoside binding to the ribosome. (ex. addition of adenyl, acetyl, or phosphoryl group via transferases) 

Genes encoding transferases are often located on mobile genetic elements(ex. plasmids) that facilitate transfer to other bacteria. 

Macrolides (erythromycin, azithromycin, clarithromycin) 

• Mechanism of action 
• Mechanism of Resistance (2) 

Bacteriostatic, Broad Spectrum 

Often used in pts with allergies to β-lactams 

Mechanisms of Action- Binds to 50s ribosomal subunit to block elongation of proteins. 

Mechanisms of Resistance: 1) Enzymatic modification(methylation) of ribosomal RNA(erm methylase gene) --> erythromycin can't bind to methylated ribosome. 

2) Efflux Pump-Can expel macrolides from cells enabling protein synthesis to continue. 

Chloramphenicol

• Toxicity
• Mechanism of Action 
• Mechanism of Resistance

Bacteriostatic . Potential toxicity (aplastic anemia) limits its use only to very severe infections (e.g. Rocky Mountain Spotted fever (wtf????) ) 

Toxicity: From lack of selectivity-inhibits ribosomes in the mitochondria. 

Mechanism of Action: Binds to the 50S ribosome subunit to inhibit peptidyl transferase activity (elongation)

Mechanism of Resistance: Chloramphenicol acetyltransferase catalyzes the addition of an acetyl group to chloramphenicol preventing ribosomal binding.  

Clindamycin

• Mechanism of Action 
• Mechanism of Resistance

Bacteriostatic, Generally inactive against Gram (-) aerobes. Used in community acquired MRSA but less effective in hospital-acquired MRSA which is usually resistant to antibiotics. Also used to treat S. aureus 

Mechanism of Action: Binds to 50s ribosomal subunit to block the elongation of proteins. 

Mechanism of Resistance: Methylation of rRNA(erm methylase gene); clindamycin cannot bind to methylated ribosome. NOTE: bacteria resistant to macrolides are resistant to clindamycin due to the presence of the erm gene. 

Linezolid

• Mechanism of Action 
• Mechanism of Reistance

Inhibitor of protein synthesis.Indicated in the treatment of complicated skin and skin structure infections caused by Staph aureus, Staph pyrogenes or Streptococcus agalactiae. Not effective against Gram (-) bacteria. High cost for oral treatment. 

Mechanism of Action: Member of oxazolidinone class and blocks entry of tRNA onto the 50S subunit.(bacteriostatic)

Mechanism of Resistance: Pt mutations in ribosomal components that prevent Linzolid binding. 

Nalidixic acid

• Mechanism of Action
• Problems/Mechanism of Resistance

Synthetic quinolone

Mechanism of Action- Binds bacterial DNA gyrase and or topoisomerase to inhibit its catalytic function--disrupts DNA replication and repair, and results in DNA damage

Problems: Narrow anti microbial spectrum: rapid selection for resistant mutants. 

Fluoroquinolones(e.g. ciprofloxacin) 

• Mechanism of Action 
• Adverse Rxns
• Mechanism of Resistance(2) 

Bactericidal, broad spectrum

Mechanism of Action: Causes dbl stranded breaks

Adverse Rxns: Recently been linked to increased risk of tendinitis and tendon rupture.

Mechanism of Resistance: 1) Pt mutations in bacterial DNA gyrase prevents antibiotic binding and render the enzyme resistant to the action of quinolones.

2)Efflux pump mediated resistance 

Metronidazole

• Mechanism of Action 

Targets DNA. Used to treat anaerobic bacterial infections; common treatment for C. difficile pseudomembranous colitis. 

Mechanism of Action: Produces radical in an anaerobic eviornment, leading to toxic metabolite that damages DNA. 

Antimetabolites: Sulfonamides and Trimethoprim

• Mechanism of Action

structurally similar to metabolic intermediates which act as competitive inhibitor to block the normal biosynthetic pathway. 

Sulfonamides: analogues of p-aminobenzoic acid

Trimethoprim: analogues of dihydrofolate-inhibits dihydrofolate reductase