Antibiotics PDF

Bacterium (Prokaryote) Nucleotides DNA Chain DNA Synthesis Helicase Separates DNA Strands Supercoiling To p o i s o m e r a s e I R e m o v e s O n e C o i l Topoisomerase II Removes Two Coils DNA Targets: Topoisomerases●Topoisomerases relax DNA and allow polymerase to read entire s...

Bacterium (Prokaryote) Nucleotides DNA Chain DNA Synthesis Helicase Separates DNA Strands Supercoiling To p o i s o m e r a s e I R e m o v e s O n e C o i l Topoisomerase II Removes Two Coils DNA Targets: Topoisomerases●Topoisomerases relax DNA and allow polymerase to read entire strand●Type I –Snips one DNA strand and relaxes one coil●Type 2 –Snips two DNA strands and relaxes two coils. Also moves replicated DNA to new daughter cell. Is the bigger target of the two topoisomerases. To p o i s o m e r a s e I n h i b i t o r s : Fluoroquinolones•Inhibit topoisomerase type II•Inhibit DNA replication•Damaged DNA induces apoptosis•Examples: ciprofloxacin, ofloxacin, levofloxacin RNA Transcription Tra n s c r i p t i o n I n h i b i t o rs : RifamycinsForm a stable complex with RNA polymerase and inhibit RNA synthesisExamples are rifampin (aka rifampicin) & rifabutin Bacterial vs. Human Ribosome Ribosome Subunits Tra n s l a t i o n a t t h e R i b o s o m e Codons & Amino Acids Tra n s l a t i o n I n h i b i t o rs•Bind to bacterial ribosomes and prevent transfer RNA binding•Prevents bacterial protein synthesis•Can also bind to mammalian ribosomes Tra n s l a t i o n I n h i b i t o rs : Aminoglycosides•Bind to 30s and induce mRNA misreading•Largely used for gram negative bacteria•Act synergistically with beta-lactams (penicillins, cephalosporins) Aminoglycoside Toxicity Mechanisms Aminoglycosides: Neuromuscular Blockade Aminoglycoside AEs•Ototoxicity –May be due to effects on mitochondrial ribosomes in inner ear hair cells•RF –Due to effects on mitochondrial ribosomes in renal tubular cells•Neuromuscular blockade –Interfere with Ca++ influx in presynaptic motor neuron Resistance to Aminoglycosides•Most common cause is bacterial enzymatic modification•Plasmid-encoded enzymes inactivate aminoglycosides via adenylation, acetylation, or phosphorylation Plasmid-Encoded Resistance Tra n s l a t i o n I n h i b i t o rs : Te t r a c y c l i n e s & M a c r o l i d e s•Te t r a c y c l i n e s b i n d t o 3 0 s a n d b l o c k tRNA binding to mRNA which interrupts peptide elongation e.g., tetracycline, doxycycline, minocycline•Macrolides bind to 50s and prevent and formation of peptide bonds between amino acids and prevent exit of nascent proteins from ribosome e.g., erythromycin, azithromycin, clarithromycin Bacterial Cell Wall: Composed of Peptidoglycans (aka murein) Bacterial Walls: Gram Positive & Negative Cells Steps in Peptidoglycan Synthesis1.Monomer synthesis2.Polymerization3.Cross-linking Polymer Cross-Linking Inhibitors of Monomer Synthesis•Fosfomycin (Monurol) –Inhibits enzyme that links protein (peptido) to sugar complexes (glycan)•Bacitracin –Inhibits dephosphorylation step in monomer synthesis Inhibitors of Monomer Polymerization•Va n co myc i n –Prevents monomer chain elongation•Can cause “red man syndrome” Vancomycin-Induced Red Man Syndrome Vancomycin-Induced Red Man Syndrome Inhibitors of Polymer Cross-Linking•Beta-lactams –penicillins, cephalosporins, cabapenems•Form covalent bonds with bacterial transpeptidases which mediate formation of cross-linkages•Synergize with aminoglycosides –they disrupt bacterial cell wall and make it more permeable to aminoglycoside entry. MOA of Inhibitors of Polymer Cross-Linking Inhibitors of Polymer Cross-Linking•Resistance can be due to reduced affinity for penicillin binding protein or plasmids that encode for beta lactamase•Mutations can alter ability of drug to bind to bacterial transpeptidase (aka penicillin binding protein) and reduce its effectiveness •Plasmids can encode for beta lactamase which cleaves beta lactam Resistance: Plasmid-Encoded Beta-Lactamase Beta-Lactamase Inhibitors•Amoxicillin-Clavulanic acid –Augmentin®•Ampicillin-Sulbactam -Unasyn®•Pipercillin-Ta z o b a c t a m –Zosyn® Fungal Structure (Eukaryote) Fungal Cell Wall & Membrane Ergosterol Synthesis Inhibitors: Azoles•Bind to and inhibit a fungal P450 enzyme involved in ergosterol synthesis•Can also bind to human enzymes e.g., P450, steroidogenesis & androgenesis enzymes•Resistance d/t P450 mutations or upregulation of drug efflux pumps Fungal Membrane Stability Inhibitors•Polyenes –Bind to ergosterol and create cell membrane pores (amphotericin & nystatin)•Liposomal delivery of amphotericin reduces AEs Liposomal Amphotericin to Reduce To x i c i t y Inhibitors of Fungal Cell Wall Synthesis: Echinocandins•Fungal cell walls composed of proteins, chitins and beta-glucans•Inhibit enzyme involved in beta-glucan synthesis•Examples are Capsofungin®, Micafungin® Influenza A Viral Lifecycle Oseltamivir (Tamiflu®)Mechanism of Action SARS-CoV-2 Replication Remdesivir MOA