Week 5 Cont - Protein Synthesis Inhibitors PDF

Overview of Unit: Week 5 (part 2) Protein synthesis inhibitors Aminoglycosides Tetracyclines Macrolides Lincosamides Streptogramins Oxazolidinones  Learning Objectives – Week 5 (part 2) 1. Describe the mechanism of action of each drug 2. Compare and co...

Overview of Unit: Week 5 (part 2) Protein synthesis inhibitors Aminoglycosides Tetracyclines Macrolides Lincosamides Streptogramins Oxazolidinones  Learning Objectives – Week 5 (part 2) 1. Describe the mechanism of action of each drug 2. Compare and contrast the structural differences among the different classes of protein synthesis inhibitors 3. Identify the spectrum of activity relative to the structure-activity relationship (SAR) of the drug 4. List their clinical uses 5. Describe their PK and PD properties that allow for their clinical utility 6. List common important ADR 7. Identify common mechanisms of drug resistance Bacterial Protein Synthesis Bacterial Protein Synthesis Ribosome moves 5’–3’ on mRNA 30S binds and decodes codon/anti-codon 30S Decoding = 50S forms peptide bonds (peptidyl transferase) 50s form peptide = bond  Protein Synthesis Inhibitors Target 30S ribosomal subunit Target 50S ribosomal subunit Aminoglycosides Macrolides Gentamicin Erythromycin Tobramycin Clarithromycin Amikacin Azithromycin Tetracyclines Telithromycin (ketolide) Doxycycline Fidaxomicin* Bind to sigma subunit. inhibit = transcription Tigecycline (glycylcycline) Lincosamides · Minocycline Streptogramins Oxazolidinones* Inhibiting Protein Synthesis  Targets 30s subunit General Features of Aminoglycosides  General Features of Aminoglycosides Derived from Streptomyces (“mycin” suffix) Amikacin derived from kanamycin Derived from Micromonospora (“micin” suffix) Structure: positively charged molecule containing two amino sugars joined by a glycosidic linkage to a central nucleus Many positively charged groups ~ gram negative Aids in binding to the negatively charged bacterial outer membrane Large molecule, but not too large Can slowly diffuse across the outer cell membrane Aminoglycoside Structure amino sugars bond > glycosidic  Aminoglycoside: MOA Concentration-dependent, bactericidal peak: MIC [High] (low] Binds 16S rRNA of 30S ribosomal subunit  Concentration-Dependent Killing Effects of Aminoglycosides 1. Low (aminoglycoside) inside the bacterial cell; high (aminoglycoside) outside the cell 1. Drug slowly diffuses through bacterial outer membrane porins 2. Transport across cytoplasmic membrane depends on a transmembrane electrical gradient O2 dependent = 2. Aminoglycoside within the cell binds to 30S ribosomal subunit—misreading "Weird of mRNA—formation of aberrant proteins proteins = " 3. Aberrant proteins insert into the membrane of the bacteria 1. Pore formation in the membrane 4. Aminoglycoside drug molecules now freely pass through these pores 1. High (aminoglycoside) within the cell: complete and irreversible inhibition of ribosome function stopping protein Synthesis = Pharmacokinetics: Aminoglycosides A: poorly absorbed from GI tract Administered parenterally or via inhalation = Not given orally D: low distribution in most tissues [High] in cells of the renal cortex and otic (does not cross BBB) tissue M: minimal to no hepatic metabolism E: mostly excreted in urine, Dosing based on renal function unchanged  Pharmacodynamics: Aminoglycosides aprane pass cytoplasmic only works D on Spectrum: aerobic gram-negative rods bacteria that Requires O2-dependent transport system across inner USE O2 membrane No activity against anaerobic bacteria Post-antibiotic effect once daily dosing : Narrow-therapeutic window therapeutic low index Pregnancy risk category: D Positive evidence of human fetal risk  Clinical Applications: Aminoglycosides ~ Synergism with cell wall-active agent Treating Pseudonomas Extend spectrum to aerobic gram-positive cocci infections Gentamicin, tobramycin, amikacin Hospital-acquired pneumonia (HAP) & Causative bacteria P Aeruginosa. Gentamicin Plague Tularemia  ADRs: Aminoglycosides Acute kidney injury Drug accumulation in proximal tubular cells (can be reversible) Ototoxicity : ear damage Vestibular or cochlear Can be permanent Neuromuscular blockage Drug competition with Ca2+; reduction in acetylcholine release; respiratory paralysis  Resistance to Aminoglycosides Plasmid-encoded production of transferases produce can enzymes that modify drug structure Adenylation, acetylation > Transferases Decreased accumulation of drug Presence of efflux pumps = keep drug [3 low Mutation of drug target Modify now Lowers affinity to 30S subunit drug looks  Targets 30s subunit General Features of Tetracyclines Y cyclic Rings  General Features of Tetracyclines Structure: four fused rings with a system of double bonds Intracellular accumulation 123 4 Enter by passive diffusion through porins Active transport across inner membrane & work on gram positive B bacteria gram negative Tetracycline Structure Glycylamido-group D overcome resistance ( mechanisms D Minocycline  Tetracycline: MOA Bind ____ 14S rRNA of ____ 30S Blocks binding of aminoacyl-tRNA to A-site N Different MOA W  Pharmacokinetics: Tetracyclines A: oral absorption impaired in the Also administered IV/IM presence of di-/trivalent cations ex Mg, cae , & Available orally D: well distributed in tissue and body Concentrate in fetal bone fluids, sequestration in bone and teeth (pregnancy risk category D) M: small amount of glucuronidated metabolites E: primarily urine; bile  Clinical Applications: Tetracyclines · gram positive gram negative, atypical , Doxycycline Broad-spectrum, bacteriostatic, concentration-dependent; AUC/MIC “Niche” indications 3 Gram-negative cholera, gram-positive anthrax, spirochete Lyme disease, Rickettsia S Pneumoniae. > M Pneumonia C Pneumonial. ,. CAP, atypical infections Drug - resistant MRSA (complicated skin and soft tissue infections [SSTIs]) Tigecycline (glycylcycline) Intra-abdominal infections (anaerobes), enterococci (VRE) MRSA (complicated SSTIs) CAP caused by multidrug-resistant (MDR) S. pneumoniae Minocycline Fyl Most commonly used for anti-inflammatory properties Acne vulgaris, RA (off-label)  ADRs: Tetracyclines UV-absorbing properties lead to cutaneous photosensitivity (sunburn) Effects on calcified tissue Enamel hypoplasia, tooth discoloration, shunted growth Avoid in pregnancy and children under eight years of age GI distress : can take wh food Esophagitis But remember dairy foods and antacids decrease oral absorption Superinfections … why? Broad spectrum antibiotic (good B bad)  Resistance to Tetracyclines Intrinsic resistance Inability of microbe to accumulate the drug Plasmid-encoded efflux pumps Tigecycline avoids these pumps Alteration of proteins that interfere with drug binding to A-site Ribosomal Protection Proteins (RPPs) : site Enzymatic inactivation -change binding Fyl Omadacycline: Third Generation Tetracycline Clinical indication Treatment of adults with: 1234 (CAP) CABP: community-acquired bacterial pneumonia ABSSSI: acute bacterial skin and skin structure infections Has activity against bacterial strains expressing the two forms of tetracycline resistance out of the cell 1. Efflux pumps found on : bacteria cell membrane = Remove drug 2. Ribosomal protection PK properties: PO/IV, not metabolized ADRs: N/V, headache, infusion site reaction, increased liver enzymes Fyl Eravacycline: Third Generation Tetracycline Clinical indication Drug Resistant Treatment of complicated intra-abdominal infections caused by gram-positive and gram-negative bacteria in patients 18 and older PK properties: IV only, hepatic metabolism ADRs N/V, infusion site reactions Targets 50s subunit Macrolides = ACT by THROwing 50s MLS TAg 30S  General Features of Macrolides s large Structure: large “macro” cyclic lactone ring to which one or more sugars are attached Erythromycin 9 1 2 6 14-membered 1 lactone ring Interacts with ribosome Azithromycin and clarithromycin are semisynthetic derivatives of erythromycin Telithromycin is a semisynthetic ketolide derivative of erythromycin derivatives of erythromycin Structures Acid stability; Better absorption, longer tissue penetration less GI upset chain side 9 Methoxy group amate 9 carb 6 12 6 1 1 12 1 Ketone group 15-membered ring sugar sugar Azithromycin Clarithromycin Telithromycin Bind to two domains interacts with 50S Ribosome in 50S subunit  Macrolide: MOA Amino sugar at position three Broad-spectrum, bacteriostatic, concentration-dependent; AUC/MIC binds 23S rRNA adjacent to the & peptidyl transferase center of a end 50S subunit Ribosome is producin -Shiftingposition set Inhibits ____________ of tRNA I Translocation from P-site to E-site, resulting in dissociation of incomplete nascent peptide Blocks ___________ Peptide bond formation > close to peptidyl transferase center  Pharmacokinetics: Macrolides A: all adequately absorbed orally Erythromycin absorption reduced by food I take on empty stomach) Erythromycin, azithromycin accumulate in MQ D: excellent lung tissue penetration and Azithromycin half-life: over 60 hours intracellular activity All concentrate in the liver M: all, but erythromycin, are converted to active metabolites E: primarily bile  ADRs: Macrolides GI intolerance > forptw/ constipation Erythromycin given as a GI stimulant Hepatitis : telithromycin Fever, jaundice, impaired liver function Cardiac Prolongation of the QT interval Ototoxicity : damage to ear tissue  Clinical Applications: Macrolides "Broad Spectrum Gram-positive - NOT MRSA Staphylococci, pneumococci, GAS Gram-negative Respiratory infections = M. Catarrhalis STIs N Gonarrhea :. Atypicals No anaerobic activity Other Lyme disease, H. pylori  Resistance to Macrolides Change in target site leads to decreased drug binding Methylation of rRNA Does not affect telithromycin 2 binding areas Mutation in 50S subunit Efflux pumps Does not affect telithromycin Production of esterases Degrade Macrolides Degrade macrolides  Novel Macrocyclic Antibiotic: Fidaxomicin (Dificid) sinhibit transcription MOA: binding to the sigma subunit of RNA polymerase PD: bactericidal, PAE equals 10 hours Narrow-spectrum: active against gram-positive aerobes and anaerobes PK: administered orally, negligible systemic absorption, minimal intestinal metabolism, high fecal concentration Clinical use: C Diff infections. ADR: N/V, GI hemorrhage  Clindamycin Lincosamide class D Lincomycin natural product of Streptomyces Clindamycin is a synthetic derivative Structure: amino acid derivative plus amino sugar MOA Resistance same as macrolides  Clindamycin (cont.) Bacteriostatic or bactericidal, concentration-dependent; AUC/MIC Spectrum: gram-positive aerobic and anaerobic Anaerobic gram-negative only ADR: C. difficile-associated diarrhea (CDAD) PK: well-absorbed orally, available IV and topical, widely distributed in many fluids and tissues, majority excreted as inactive metabolite in feces/bile Clinical applications: intra-abdominal infections, toxic shock therapy, skin and soft tissue infections  Quinupristin/Dalfopristin (combo product) Streptogramin A and B : Target 50S subunit Synergistic antibiotic isolated from Streptomyces Structure: macrocyclic compounds Spectrum: gram-positive only Clinical applications: MRSA, VRE, 30:70 Streptogramin B penicillin-resistant pneumococci * PK: IV formulation ADR: pain and phlebitis at the infusion site, arthralgias, and myalgias Streptogramin A  Quinupristin/Dalfopristin: MOA Bacteriostatic separately, bactericidal together, concentration-dependent; AUC/MIC long PAE Dalfopristin induces conformational change in 50S enhancing binding of quinupristin Binding site = Binding to different sites on the 50S bacterial ribosomal subunit, thereby inhibiting protein synthesis Resistance: modification of binding site, enzymatic W inactivation of drug, efflux pumps Similarise in synthetically made Oxazolidinone: MOA Bind to the ________ 235 of ____ URNA to prevent formation of functional ___ 70S initiation complex Resistance: efflux pumps, a single AA mutation in 23S rRNA of 50S  First Generation Oxazolidinone: Linezolid Completely synthetic Thick cell · Gram-positive infections only Wall 23SRNA Bacteriostatic or bactericidal depending on infection A Time-dependent, bactericidal for Streptococcus infections Allows cell Bacteriostatic for Staphylococcus and Enterococcus infections wall penetration Clinical application Resistant gram-positive infections (MRSA, VRE, penicillin-resistant S. pneumoniae) PK: PO/IV administration ADRs: thrombocytopenia, serotonin syndrome when given with other serotonin agents Fyl Second Generation Oxazolidinone: Tedizolid MOA: same as linezolid, but has activity 235 against mutated 23S rRNA URNA Gram-positive infections only Similar spectrum to linezolid A Clinical applications Allows cell skin infection ABSSSI caused by linezolid-resistant MRSA wall penetration Retains activity against Cfr methyltransferase mutation to the 23S rRNA PK: PO/IV availability ADRs: N/V/D, C. difficile pseudomembranous colitis