Antibiotics Antifungals and Antivirals Aditi Reddy 240319 ANTIBIOTICS

Antibiotics, Antifungals and Antivirals Aditi Reddy 24/03/19

ANTIBIOTICS Learning Objectives Antibiotic classes: identify the main classes of antibiotic drugs and distinguish between them in terms of mechanism of action. Antibiotic resistance: recall the mechanisms commonly used by bacteria to become resistant to drugs

LO - Antibiotic classes: identify the main classes of antibiotic drugs and distinguish between them in terms of mechanism of action. • 2 main mechanisms of action that you need to know: 1) Drugs that target bacterial protein synthesis 2) Drugs that target bacterial cell wall synthesis

Bacterial Protein Synthesis Nucelic Acid Synthesis PABA DHOp DHF THF DNA Replication DNA gyrase + RNA polymerase Ribosomes Produce protein from RNA templates Differ from eukaryotic ribosomes

DRUGS • Sulphonamide – inhibits DHOp synthase • Trimethoprim – inhibits DHF reductase • Fluoroquinolones (e. g. ciprofloxacin) inhibit DNA gyrase and topoisomerase IV • Rifamycins (e. g. rifampicin) inhibits bacterial RNA polymerase • Ribosomes are inhibited by: • • Aminoglycosides (e. g. Gentamicin) Chloramphenicol Macrolides (e. g, erythromycin) tetracyclines

Bacterial Cell Wall Synthesis 1. Pentapeptide is created on NAM 2. NAM and NAG associate forming Pt. G 3. Pt. G is transported across the membrane by bacroprenol 4. Pt. G is incorporated into the cell wall when transpeptidase enzyme cross-links Pt. G pentapeptides

DRUGS • Glycopeptides e. g. vancomycin bind to the pentapeptide preventing Pt. G synthesis • Bacitracin inhibits bactoprenol regeneration preventing Pt. G transportation • B-lactams bind covalently to transpeptidase inhibiting Pt. G transportation • E. g. carbapenems, cephalosporins, penicilins • Lipopeptide e. g. daptomycin disrupts Gram +ve cell walls • Polymixins bind to LPS and disrupts Gram –ve cell membranes

LO - Antibiotic resistance: recall the mechanisms commonly used by bacteria to become resistant to drugs • 5 main mechanisms of drug resistance that you need to know: 1) Production of destruction enzymes 2) Additional target 3) Alterations in target enzyme 4) Hyperproduction 5) Alterations in drug permeation

1) Production of destruction enzymes • Some bacteria produce B-lactamases • Hydrolyses the C-N bond of the B-lactam ring • Confers antibiotic resistance Examples: • Pencillin G and V • Flucloxacillin and Temoxillin • Amoxicillin (+clavulanic acid)

2) Additional target • Bacteria produce another target that is unaffected by the drug Example: E. coli produces a different DHF reductase making it resistant to trimethoprim

3) Alterations in target enzyme • The original target of the antibiotic is altered • Antibiotic is no longer effective

4) Hyperproduction • Bacteria significantly increase levels of DHF reductase • Essentially bacteria overproduce enzmyes in the hope that the antibiotic will become less effective • This is not sustainable for the bacteria

5) Alteration in drug permeation • Some antibiotics will use aquaporins to enter the bacterium • The bacterium reduces aquaporins and increases efflux systems • Net effect is to stop antibiotic from entering and effluxing any amount that has made it inside the bacterium

ANTIFUNGALS Learning Objectives Antifungals: differentiate between the drugs used to treat fungal infections.

Antifungal Drugs • 2 drug classes that you need to know: • Azoles (Fluconazole) • Polyenes (Amphotericin) • Azoles – prevent sterol synthesis • Polyenes – interact with cell membrane sterols forming membrane channels

ANTIVIRALS Learning Objectives Viral physiology: summarise how viruses use the host cell to replicate. Antiviral drugs: summarise the mechanism of action of anti-viral drugs used in the treatment of HIV, hepatitis, herpes and influenza.

Viral physiology: summarise how viruses use the host cell to replicate.

Antiviral drugs: summarize the mechanism of action of antiviral drugs used in the treatment of HIV, hepatitis, herpes and influenza. • HIV • Hepatitis • Herpes • Influenza

Viral Hepatitis • Both Hep B and C have a tropism for liver hepatocytes • Hep B = not curable • Hep C = curable • For Hep B – contain the viral replication and transform it into a chronic disease • If someone gets infected with Hep B or C wait for 6 months to see if it naturally clears • A lot of people can clear Hep B and C before they get a chronic infection

Treatment Hep B • Tenofovir – nucleotide analogue (nucleotide reverse transcriptase inhibitor) • Sometimes given with peginterferon alpha Hep C • Ribavirin and peginterferon alpha • Ribavirin is a nucleoside analogue • Boceprevir – protease inhibitor

HIV Life Cycle Attachment and Entry • Viral membrane proteins interact with leukocyte membrane receptors • Viral capsid endocytosis Replication and Integration • Within cytoplasm – reverse transcriptase enzyme converts viral RNA DNA • DNA transported into nucleus and integrated into host DNA Assembly and Release • host cell machinery utilized to produce viral RNA and essential proteins • Virus is assembled within cell mature virion is released

Treatment Attachment and Entry • HIV glycoprotein 120 attaches to CD 4 receptor • GP 120 also binds to either CCr 5 or CXCR 4 • GP 41 penetrates host cell membrane and viral capsid enters Enfuvirtide – binds to HIV GP 41 transmembrane glycoprotein Maraviroc – blocks CCR 5 chemokine receptor

Treatment Replication • Reverse transcriptase: viral singlestranded RNA converted to double stranded DNA Nucleoside RT inhibitors e. g. zidovudine Nucleotide RT inhibitors e. g. tenofovir Non-nucleoside RT inhibitors • No phosphorylation required • Not incorporated into viral DNA • E. g. efavirenz Integration • Viral integrase inserts viral DNA into host DNA • Raltegravir – first of 3 licensed integrase inhibitors

Treatment Assembly and Release • Gag precursor encodes all viral structural proteins • HIV protease cleaves Gag precursor protein • Protease inhibitors (PI) • Saquinavir – 1 st generation • Low dose ritonavir reduces PI metabolism

Herpes Simplex Virus Virology • Double stranded DNA • Surrounded by tegument and enclosed in a lipid bilayer Tropism • Herpes simplex virus (HSV)-1 cold sores • HSV-2 genital herpes Treatment • Nucleoside analogues acyclovir

Influenza Virology • Multipartite single stranded RNA virus • Envelope protein neuroaminidase is important in the release of the virus into the host cell Tropism • Nose, throat, bronchi Treatment • Neuraminidase inhibitor oseltamivir

Question time!

Q 1 Beta-lactams are a large group of antibiotics – which of the following is a beta-lactam antibiotic? a) Carbapenem b) Glycopeptide c) Lipopeptide d) Macrolide e) Sulphonamide