PSCI 412: ID final

Sulfonamides

• Inhibit the synthesis of folic acid by competitive inhibition of dihydropteroate synthase

• Leads to reduced synthesis of DNA and of certain amino acids

Trimethoprim

• Inhibits dihydrofolate reductase (DHFR)

Quinolones and Fluoroquinolones

• Inhibit the activity of bacterial type II topoisomerase by forming stable DNA/topoisomerase/drug complexes

• Two topoisomerase participate in DNA replication in bacteria (DNA gyrase and topoisomerase IV)

  • DNA gyrase

    • Primary target of fluoroquinolones in Gram - bacteria

  • Topoisomerase IV

    • Primary target of fluoroquinolones in Gram + bacteria

• Inhibition of these enzymes result in bacterial cell death (bactericidal effect)

Ciprofloxacin

• Adequate serum and tissue concentration. Good for systemic infections

• Active against Gram - and Pseudomonas, weak against Streptococcus pneumonia

• No activity against anaerobic bacteria

Levofloxacin

• Adequate serum and tissue concentration. Good for systemic infections

• Active against Streptococcus pneumonia and atypical bacteria (Legionella, Chlamydia, Mycoplasma), less activity against Pseudomonas than Generation II

• Active against some anaerobic bacteria

Fluoroqinolones (Adverse effects)

• 3-17% mild GI tract symptoms (nausea, vomiting, diarrhea…)

• 0.9-11% headache, dizziness

Fluoroquinolones (Black Box Warning)

• Tendon rupture and damage

• Risk of permanent peripheral neuropathy

• Central nervous system effects

• Exacerbation of myasthenia gravis

Nitrofurantoin

• Formation of nitroso groups (-N=0)

• DNA, RNA and protein damage

Main steps of the peptidoglycan synthesis

• Cytoplasm

  • Formation of NAM from NAG

  • Addition of 3 AA to NAM

  • Addition of the D-Ala-D-Ala dipeptide to the existing NAM-tripeptide

  • Complex formation with Bactoprenol

  • Addition of NAG to NAM/pentapeptide/bactoprenol

  • Addition to 5 Gly to Lys (position 3) in Gram + bacteria

  • Transfert of the NAG/NAM-pentapeptide/bactoprenol to the periplasmic space

• Periplasmic space

  • Elongation of the NAG/NAM chain by transglycosylation

  • Cross-linking of the peptidoglycan through the action of transpeptidase

Fosfomycin

• Inactivates enolpyruvate transferase (MurA)

  • Prevents the formation of NAM from NAG

Cycloserine

• Inhibits alanine racemase and D-Ala-D-Ala formation

  • Inhibits the formation of the pentapeptide

Cycloserine (adverse effects)

• Serious CNS toxicity (50% patients)

• “Psych-serine”

Bacitracin

• Inhibits the dephosphorylation of bactoprenol by a phosphatase

  • Inhibits translocation of the NAM-pentapeptide to the other side of the membrane

Vancomycin

• Binds to D-Ala-D-Ala and hinders the cross-linking of the peptidoglycan and the elongation of peptidoglycan strands

  • Blocks the access of the transglycoslase and of the transpeptidase to the D-Ala-D-Ala dipeptide

Vancomycin (Indications)

• Active against Gram + bacteria only

• Active against MRSA (Methicillin Resistant Staphylococcus aureus) infections

Vancomycin (Adverse effects)

• Most frequent adverse effects

  • Dizziness

  • Hypersensitivity (red man syndrome)

    • Triggers the release of histamine from mast cells

• Most serious adverse effects (at higher doses)

  • Dose-related nephrotoxicity

  • Ototoxicity has been described

Vancomycin (Resistance)

• D-Ala-D-Ala changed to D-Ala-D-Lactate or D-Ala-D-Serine

Dalbavancin

• Dimerize and anchor their lipid moiety into the cytoplasmic membrane

• Disrupts the bacterial cell membrane

• Binds to D-Ala-D-Ala and hinders the cross-linking of the peptidoglycan and transglycosylation reaction

• Improved efficacy compared to vancomycin

Daptomycin

• Binds to bacterial cytoplasmic membrane

• Forms a complex with calcium ions resulting in pore formation and membrane depolarization

• Results in arrest in DNA, RNA and protein synthesis and cell death

Beta-lactams

• Inhibition of the bacterial transpeptidase

  • The beta-lactam drug acetylates the bacterial transpeptidase

  • The transpeptidase is inactive

  • The peptidoglycan cannot be cross-linked

Define a Penicillin Unit

• One milligram of pure penicillin G sodium corresponds to 1,667 units

  • One unit is the specific activity contains in 0.6ug of crystalline penicillin sodium (MW=356g/mol)

Penicillin and Cephalosporin (adverse effects)

• Hypersensitivity (0.7-10%)

• Change in composition of the intestinal microbiome

Beta-lactamase (mechanisms of resistance)

• Chromosomal or plasmid encoded

• Constitutive or inducible expression

• Serine or Zinc based catalytic activity

1st generation cephalosporins

• Cephalexin

• Cefazolin

2nd generation Cephalosporins

• Cefuroxime

3rd generation of cephalosporins

• Cefdinir

• Ceftriaxone

4th generation of cephalosporins

• Cefepime

Ceftriaxone (adverse effects)

• Risk of kidney stones

• Clostridium Difficile associated diarrhea

Ceftriaxone (drug interaction)

• Ca2+ ceftriaxone forms complexes in urine

• Drugs and calcium containing solution should NOT be co-administered

Carbapenems (adverse effects)

• Cross allergy with penicillins

• Can induce seizure

Carbapenems

• Broader spectrum of activity than the penicillins

• Same mechanism of action as penicillins and cephalosporins

• Resistant to many Beta-Lactamases, but not to all

Aminoglycosides (30S)

• Blocks the initiation of the translation

• Slow-down or terminate initiated synthesis

• Leads to insertion or incorporation of incorrect amino acids

Aminoglycosides (adverse effects)

• Vestibular and auditory dysfunction

• Nephrotoxicity

• Neuromuscular blockade

• Should not be used in pregnant women

Aminoglycosides (Resistance)

• Aminoglycoside modifying enzymes

  • Results in acetylation, phosphorylation, adenylation of the OH groups of the drug

• Impaired transport

• Mutations in ribosomes

Aminoglycosides (examples)

• Gentamicin

• Neomycin

Tetracyclines (30S)

• Block the access of the tRNA to the ribosome

• Binds to 30S

• Protein translation is stopped

Tetracyclines (adverse effects)

• Frequent

  • GI irritation: epigastric burning, nausea, vomiting, diarrhea, dizziness, vertigo

    • Effects are reduced when taking the drug with food, but dairy products and antacids should be avoided

  • Photosensitivity

  • Hepatotoxicity

• Serious

  • Permanent brown tooth staining in children

Tetracycline (example)

• Minocycline

• Doxycycline

Lincosamides (50S)

• Inhibits peptide bound formation between nascent peptide and the new AA

Lincosamides (examples)

• Clindamycin

Lincosamides (adverse effects)

• Diarrhea

  • Clostridium difficile associated diarrhea

• Skin rashes

Lincosamides (drug resistance)

• Ribosomal protection - MLSb phenotype

• Efflux pumps

• Drug inactivation

Macrolides (50S)

• Inhibits translocation of the ribosome from the A site to the P site

  • Terminates protein synthesis

Macrolides (example)

• Azithromycin

Macrolides (Drug Interaction)

• Inhibition of CYP3A4

  • Significant inhibition of P450s with erythromycin and clarithromycin

    • Potentiate the effects of carbamazepine, corticosteroids, cyclosporine, digoxin, ergot alkaloids, theophylline, triazolam, valproate and warfarin

    • CYP3A4 inhibitors (itraconazole) increase peak serum concentrations of clarithromycin

  • Weak with azithromycin

Macrolides (mechanism of resistance)

• Expression of a methylase that modifies the binding sites of the drug on the ribosome

  • MLSb phenotype

• Ribosomal mutation

• Drug efflux by active pump mechanisms

• Hydrolysis by esterases

Linezolid (50S)

• Inhibits initiation of translation

• Binds to P site of the 50S ribosomal subunit and prevents initiation of protein synthesis

Linezolid (adverse effects)

• Myelosuppresion

  • Thrombocytopenia

• Peripheral neuropathy

• Optic neuritis

• Lactic acidosis

Linezolid (drug interaction)

• Weak inhibitor of monoamine oxidase

  • Effect on serotonin, melatonin, ephedrine and dopamine levels

Linezolid (Indications)

• Gram + bacteria

• MRSA, VRE, VRSA

• Should be reserved to treat multiple drug-resistant bacterial infections

Linezolid (resistance)

• Mutations in ribosomal RNA

  • Decreased binding affinity for the drugs

Describe Latent TB

• TB lives but doesn’t grow in the body

• Doesn’t make a person feel sick or have symptoms

• CAN’T spread from person to person

• Can advance to TB disease

Describe TB disease

• TB is active and grows in the body

• Makes a person feel sick and have symptoms

• CAN spread from person to person

• Can cause death if not treated

Treatment for latent TB

• 6-9 months with isoniazid

Treatment for active TB

• 6 months of treatment

  • 2 months with “RIPE”: intensive phase

    • Rifampin

    • Isoniazid

    • Pyrazinamide

    • Ethambutol

  • 4 months: continuation phase

    • Isoniazid

    • Rifampin

What is Multi Drug Resistance (MDR)

• Resistant to isoniazid and rifampin/rifampicin (first line anti-TB drugs)

What is X (extensively) Drug Resistance (XDR)

• Resistant to isoniazid, rifampin/rifampicin, at least one fluoroquinolone and one of the three injectable TB drugs amikacin, kanamycin or capreomycin

Isoniazid

• Prodrug

• Converted into a reactive nicotinoyl radical by bacterial catalase-peroxidase (KatG)

  • Radical reacts with NAD+ and NADP+

    • Nicotinoyl/NAD adducts inhibit enzymes that catalyze the synthesis of mycolic acid

    • Nicotimoyl/NADP adducts inhibit bacterial DHFR

  • Inhibits synthesis of mycolic acid and bacterial dihydrofolate reductase

Isoniazid (adverse effects)

• Hepatotoxicity

• Peripheral neuropathy

• Hypersensitivity reaction

• Convulsions in patients with seizure disorders

Pyrazinamide

• Pro-drug

• Must be converted into pyrazinoic acid (POA) by bacterial enzyme

• Leads to intracellular acidification and reduced energy metabolism by bacteria

Pyrazinamide (adverse effects)

• Hepatic disease

• Production of high levels of uric acid in tissues

  • Gout attack

Rifampin

• Inhibits DNA dependent RNA polymerase (transcription)

Rifampin (adverse effects)

• Frequent

  • Nausea and vomiting

  • Rash

  • Fever

  • Red-orange coloration of skin, urine, feces, saliva, tears, and contact lenses

• Serious

  • Possibility of severe hepatic disease in patients with chronic liver disease, alcoholism and old age

Ethambutol

• Inhibits arabinosyl transferase

• Disrupts transfer of arabinose into arabinogalactan biosynthesis, which in turn disrupts the assembly of mycobacterial cell wall

Populations at risk for fungal infections

• Patients with compromised immune system

• Surgical and intensive care unit patients

• Patients with prosthesis

Amphotericin B

• Disruption of membrane structure

Amphotericin B (adverse effects)

• Common

  • Chills and fever during infusion reaction

  • Hypoxia, hypotension

• Serious

  • Nephrotoxicity

    • C-AMB most nephrotoxic

      • Toxicity reduced when 1L saline is injected to the patient

    • Other formulations are less nephrotoxic

Azole

• Inhibits the synthesis of ergosterol by inhibiting C14-demethylase

  • C14-demethylase is the product of the gene ERG11

• C14-demethylase is an enzyme which has structural similarities with cytochrome P450

  • Many azole-based drugs bind to and modulate P450s

  • Drug interactions are common

Azole (example)

Fluconazole

Fluconazole (drug interaction)

• Substrates of CYP 3A4

Fluconazole (adverse effects)

• Nausea

• Vomiting

• Abdominal pain

• Diarrhea

• Headache

• Rash

Allylamines

• Inhibit the synthesis or ergosterol by inhibiting the enzyme squalene epoxidase

  • Squalene epoxidase is the product of the gene ERG1

Allylamine (example)

• Terbinafine

Echinocandins

• Inhibits the synthesis of the cell wall by inhibiting the 1,3-beta glucan synthase

Echinocandins (example)

Micafungin

Oseltamivir

• Inhibits influenza A and B neuraminidase

• Transition state analog of sialic acid

Baloxavir

• Inhibits the initiation of the transcription of viral mRNA

  • Endonuclease inhibitor: inhibits CAP-dependent influenza PA endonuclease. This results in:

    • Absence of generation of CAP-primers by the virus from an existing pool of mRNA molecules of the host

    • Inhibition of RNA-dependent replication of viral mRNA

    • The proteins of the virus cannot be translated because the mRNA of the virus cannot be synthesized

Nucleotide

• Phosphate group

• Sugar

• Nitrogenous base

Nucleoside

• Sugar

• Nitrogenous base

Acyclovir-Valacyclovir

• Phosphorylation by

  • 1: viral thymidine kinase

  • 2: host protein kinase

• Inhibits viral DNA polymerase and to lesser extent host DNA polymerase

• Competitor of deoxy-Guanosine-Tri-Phosphate (dGTP)

• Incorporated into viral DNA and acts as chain terminator

Acyclovir-Valacyclovir (adverse effects)

• Generally well tolerated

• Acyclovir

  • Headache, nausea, diarrhea, rash

  • Nephro and neuro-toxicities when given by IV

• Valacyclovir

  • Similar to those of acyclovir with more nephro- and CNS-toxicities

Acyclovir-Valacyclovir (resistance)

• Impaired production of viral thymidine kinase. Altered TK substrate specificity or altered viral DNA polymerase

Cidofovir

• Does not require phosphorylation by viral thymidine kinase

• Is phosphorylated yo an active (tri)-phosphate form by cellular enzymes. Inhibits viral DNA synthesis:

  • Competitive inhibitor of viral DNA polymerase

  • Competes with dCTP

  • Does only minimally inhibit host DNA polymerase

• Synergistic effect with ganciclovir or foscarnet

Cidofovir (adverse effects)

• Nephrotoxicity

Foscarnet

• Inhibits HSV DNA polymerase

• Binds to the pyrophosphate binding site

• Inhibits the cleavage of pyrophosphate from deoxynucleotide triphosphate

Foscarnet (adverse effects)

• Nephrotoxicity, hypocalcemia, CNS effects

Docosanol

• Blocks fusion between the cellular membrane and viral envelope

Tocilizumab

• Binds to IL-6 receptor, resulting in suppression of IL-6 dependent signaling pathways, reduced expression of inflammatory cytokines and reduced immune response

Baricitinib

• Inhibits Janus Kinase (JAK) resulting in decreased transcription and translation of cytokines, and decreased immune response

Tocilizumab (black box warnings)

• Risk of infection, patients should be tested for TB

• Higher risk of certain cancers (lymphoma)

Baricitinib (black box warning)

• Heart attack or stroke

• Cancer

• Blood clots

• Death

Remdesivir

• Nucleotide analog

• Prodrug

  • Needs to be phosphorylated into Remdesivir-P-P-P

• Targets RNA dependent RNA polymerase (RdRp) of the virus

Paxlovid

• Nirmatrelvir

  • Inhibits the protease of the virus

• Ritonavir

  • Inhibits the metabolism of Nirmatrelvir. Allowing it to stay in the body longer

Tenofovir

• Acts as a competitor for viral DNA polymerase and reverse transcriptase. It is also a chain terminator of viral DNA synthesis

• Needs to be phosphorylated into the di and tri-phosphate form by cellular kinase

Tenofovir (warning)

• Risk of lactic acidosis

Interferon-alpha

• Cytokine produced in response to viral infection by many cells

  • Stimulates the cytotoxic activity of lymphocytes, natural killer cells and macrophages

  • Stimulates the expression of anti-viral enzymes that degrade RNAs and inhibit viral protein synthesis

Interferon-alpha (adverse effects)

• 30% patients experience Flu like symptoms (fever, malaise, fatigue, muscle pain)

• Neurotoxicity

• Myelosuppresion

• Auto-immune disorder (symptoms)

• Cardiovascular effects

Sofosbuvir

• Pro-drug

• Uridine analogue

  • Is converted into uridine tri-phosphate analogs by cellular kinases

• Inhibits HCV RNA polymerase

  • Inhibits RNA replication by chain termination

  • Does not inhibit host RNA polymerase, DNA polymerase or mitochondrial RNA polymerase

What does DAA stand for

• Direct-acting antiviral therapy

What does HAART stand for

• Highly Active Anti-Retroviral Therapy