Antibacterials and Tuberculosis

• What is the history behind chemotherapy and antibiotics?

  Discovered by Erlich in early 20th century

  Chemotherapy = synthetic chemicals

  1928 - Alexander Fleming discovers penicillin

  Selectively toxic

  Not harmful to host

  Antibiotics = substances produced by some microorganisms or synthetical chemicals
• Describe the structure of an antibacterial cell

  Cell wall made of peptidoglycan (except Mycoplasma)

  Plasma membrane made of phospholipid bilayer and proteins

  Cytoplasm

  No presence of mitochondria or nucleus

  Single chromosome

  Outer membrane - Gram's stain (methyl violet) - can be Gram-positive or Gram-negative
• When a drug has selective toxicity, what areas are generally targeted?

  Cell wall

  Cytoplasmic membrane

  Protein synthesis

  Nucleic acid metabolism - direct or indirect
• Define bacteriostatic. Give some examples of bacteriostatic drugs

  inhibits bacterial multiplication, like:

  Sulfonamides

  Tetracycline

  Chloramphenicol
• Define bactericidal. Give some examples of bactericidal drugs.

  Kills bacteria, like:

  Penicillins

  Aminoglycosides

  Rifampicin
• Define minimum inhibitory concentration (MIC)

  Min concentration of antimicrobial capable of inhibiting growth of organism
• Define minimum bactericidal concentration (MBC)

  Lowest concentration that kills pathogen
• What types of drugs target the plasma membrane?

  Polymyxins

  Polymyxin B

  Colistin

  Lipopeptide

  Daptopmycin
• What types of drugs target the 30S subunit of ribosomes?

  Aminoglycosides

  Tetracyclines
• What types of drugs target the 50S subunit of ribosomes?

  Macrolides

  Lincosamides

  Chloramphenicol

  Oxazolidinones
• What types of drugs target folic acid synthesis?

  Sulfonamides

  Sulfones

  Trimethoprim
• What drug targets mycolic acid synthesis

  Izoniazid
• What type of drugs targets DNA synthesis? Give examples of drugs in this category

  Fluoroquinolones:

  Ciprofloxacin

  Levofloxacin

  Moxifloxacin
• What type of drugs targets RNA synthesis. Give an example of a drug in this category

  Rifamycins:

  Rifampin
• What types of drugs target beta-lactams in the cell wall?

  Penicillins

  Cephalosporins

  Monobactams

  Carbapanems
• What drug targets glycopeptides in the cell wall?

  Vancomycin
• Describe a class I drug target

  Not so good target - energy from glucose/carbon source converted to ATP then to basic carbon compounds
• Describe a class II drug target

  Better target - basic carbon compounds from Class I + energy to make:

  Small molecules

  Amino acids

  Nucleotides

  Phospholipids

  Amino sugars

  Carbohydrates

  Growth factors
• Describe a class III drug

  Good target - small molecules from Class II to make:

  Macromolecules

  Proteins

  RNA

  DNA

  Polysaccharides

  Peptidolglycan
• Give an example of a class II drug target

  Folate biosynthetic pathway

  Folate synthesis in lots of bacteria species

  Humans can't synthesise folate

  Sulfonamides inhibit folate synthesis

  Trimethoprim inhibits folate utilisation

  Sulfonamide + trimethoprim = co-trimoxamzole which is active against Pneumocystis jirovecii
• Describe peptidoglycan synthesis of Class III drug targets

  Macromolecules can't be taken up

  Peptidoglycan = sensitive synthesis (drug target)

  N-acetylglucoamine (NAG) and N-acetylmuramic acid (NAM) alternate

  Attached peptide side chains to NAM - cross linked with peptides (differ in bacterial species) making polymeric lattice

  Beta-lactam antibiotics:

  Examples:

  Penicillins

  Cephalosporins

  Monobactams

  Carbapanems

  Covalently bind w penicillin-binding proteins

  So cross linking peptides won't bind to tetrapeptide side chain

  Vancomycin - binds to D-alanyl-D-alanine terminus of cell wall precursor units

  Bacitracin

  Cycloserine
• Describe class III drug target protein synthesis

  Ribosomes hav 50S and 30S subunits, A, P and E binding sites for tRNA

  Messenger RNA (mRNA) = template

  Transfer RNA (tRNA) transfers amino acids to ribosome

  Transcription - mRNA from DNA - 30S subunit - 50S + 30S = 70S subunit

  Codons from A to P binding sites

  Tetracyclines - compete to tRNA form site A on ribosome so tRNA can't reach site A

  Aminoglycosides cause abnormal complementary base pairing between tRNA and mRNA so there's erroneous reading of mRNA

  Chloramphenicol - transpeptidation - transfer of peptide chain from tRNA on site R to tRNA at site A inhibited

  Macrolides and fusidic acid = translocation - tRNA w growing peptide chain moving from site A to site P inhibited
• Describe nucleic acid synthesis of class III drug targets

  Cell division and gene expression

  Inhibition of nucleotide synthesis - sulfonamides and trimethoprim

  Modification of base pairing of DNA template - proflavine

  DNA/RNA polymerase inhibition - rifampicin binds to bacterial RNA polymerase

  DNA gyrase inhibition - ciprofloxacin and norfloxacin
• What is tuberculosis?


  Bacterial infection caused by Mycobacterium tuberculosis complex

  Inhalation of small droplets from infected person who coughs or sneezes

  3 year average incidence of TB in 2017-2019 was 8.6/100,000 people

  WHO definitions of low incidence country = 10/100,000 people
• What are the risk factors for TB?

  Born in high prevalence areas like India, Pakistan and Somalia

  Close contacts of person w active pulmonary TB

  Had previous (mainly incomplete) treatment for TB

  Have:

  HIV

  Diabetes mellitus

  Chronic kidney disease

  Previous gastrectomy

  Occupational lung disease

  Solid organ transplants

  Taking prolonged courses of:

  Corticosteroids

  Chemotherapy

  Anti-tumour necrosis factor-alpha drug treatment

  Homeless, institutionalised or living in prison w overcrowded conditions

  Problems w alcohol or drug misuse
• What is pulmonary TB?

  More commonly occurring

  Persistent productive caught, maybe with breathlessness and haemoptysis
• What is extrapulmonary TB?

  Symptoms specifically located to sites outside of lungs or tracheobronchial tree

  Can affect lymph nodes

  Bone or joint pain

  Abdominal pain

  Confusion and headache

  Skin lesions

  Chest pain

  More common in:

  Children

  People from countries w high TB prevalence

  People w weakened immune system
• What is latent TB?

  Infected without symptoms

  Bacteria present in body but immune system can prevent infection spreading in body

  Not infectious to other people

  Active TB can occur if immune system suppressed
• Describe the pharmacotherapy of TB

  Ethambutol - active against mycobacteria, bacteriostatic

  Pyrazinamide - active in acid conditions, especially in macrophages

  Rifampicin inhibits RNA polymerase

  Isoniazid - active against mycobacteria, bacteriostatic
• What drugs can you use to treat active TB?

  Isoniazid

  Pyridoxine

  Rifampicin

  Pyrazinamide

  Ethambutol
• What drugs can you use to treat latent TB?

  Isoniazid

  Pyridoxine

  Rifampicin
• What do you do for patients with CNS TB?

  CNS TB = offer course of corticosteroid when initiating anti-TB therapy

  Pericardial TB = offer course of oral prednisolone when initiating anti-TB therapy
• What do you do for patients who have active TB without involvement of the CNS?

  Intensive phase (2 months to reduce bacterial load) - rifampicin, isoniazid (with pyridoxine), pyrazinamide and ethambutol

  Continuation phase (4 months but longer if CNS involvement) - rifampicin and isoniazid (with pyridoxine)
• What are the second line drugs for TB?

  If infection due to resistant bacteria or side effects not tolerable from first line drugs

  Aminosalicylic acid

  Amikacin

  Capreomycin

  Cycloserine

  Azithromycin and clariththromycin

  Moxifloxacin

  Protionamide (prothionamide) - not in UK market

  Bedaquiline

  Delamanid
• What drugs is MDR-TB resistant to?

  Isoniazid

  Rifampicin
• What drug is XDR-TB resistant to?

  Isoniazid

  Rifampicin

  Any fluoroquinolone

  Any of the 3 second-line injectables:

  Amikacin

  Capreomycin

  Kanamycin