Week 8 Flashcards
What is an overview of mycobacteria?
Mycobacteria are Actinobacteria (Gram positive) that belong to the suborder of Corynebacterineae
Corynebacterineae are very common in the environment
What are examples of mycobacteria?
Mycobacterium tuberculosis (M-TB) (tuberculosis- TB)
Mycobacterium leprae (leprosy)
Mycobacterium bovis (bovine tuberculosis)
What is an overview of mycobacterial cell wall?
Mycobacteria have very different cell walls to Gram positives
Most components - essential for cell survival or pathogenicity
What constitutes mycobacterial cell wall?
Thin peptidogycan layer
Arbibo-glycan layer
Mycolic acid
Glycolipids (50 to 60 layers in Tuberculosis)
Capsule with free lipids and carbohydrates, often the thickest layer
What is an overview Mycobacterium tuberculosis has had on history?
One of the biggest killers in recorded history
In the early 1900s, TB killed one out of every seven people living in the United States and Europe.
Nespaheran priest of Amun - Egpytian mummy from 21st dynasty 1000 BC
Killed George Orwell
No cure pre-1950
How many people died of Tuberculosis in 2022?
1,300,000
What is an overview of TB infection?
M-TB is a very slow growing species (doubling time of 12 -24 hours)
Inhaled in aerosols coughed out by an infected person
What is an overview of the lifecycle of TB?
90-95% can be contained in granulomas
Granulomes can become a latent infection
5-10% are active disease
When active disease can transmit
What can cause TB to reactivate?
Due to HIV, malnutrition, stress, smoking, other infectious diseases
How does TB infect people?
M-TB divides within macrophages
Granulomas form when the immune cells surround infected macrophages though Tb may stimylate this to protect from immunity
M-TB is spread if the granuloma becomes necrotic
Necrotic granulomas accumulate within the lungs, leading to death
What is an overview of macrophages role?
The role of macrophages is to engulf and destroy foreign material, including microbes
Normally, cells become trapped in the phagolysosome and are killed through acidity induced via a recruited ATPase pump, reactive oxygen species and specialised enzymes
How can TB protect against macrophage phagolysome death?
Various cell wall components and secreted proteins prevent phagolysosome formation and protect M-TB against reactive oxygen species and free radicals
What are TB molecules used to protect against macrophages?
Cell-wall glycolipids = Inhibitd PI3P deposition (I3P is involved in endocytosis and vesicular trafficking toward the lysosome)
Glutathione - Scavenges free radicals
Protein Kinase G - Inhibits phagosome lysosome fusion
PhoP - Two-component system associated with pathogenesis
What is the pathogenesis of active TB?
Gradual loss of lung function
Leads to fevers, chills, weight loss (consumption)
Chest fills up with liquid leading to death
What is an overview of TB stages?
Infection of apical alveoli, modulate macrophages and disrupt surfactant
Bronchial obstruction stasis
Post obstructive lipid pneumonia
Broncial spread of infection
Rapid development of caseaos pneumonia with symptoms of community acquired pneumonia
What can happen after rapid development of caseaos pneumonia?
Softening and fragmentation to cough out pieces of lung or
Caseation becomes dry and firm
What happens after Softening and fragmentation form from TB?
Thin walled cavity –> MTB gorw as surface pellicle to be coughed out (holes in lung TB can spread around body)
Thin wall are form granulomas around caseation
What happens after caseation becomes dry and firm from TB?
Granulomas form around caseation
Fibrocaseous tuberculosis
Granulomas around caseation can from thin wall
How many people do you think have latent TB?
About 30% of the world’s population
How common is TB?
1/3 of global population are infected TB
10% will go on to form active TB
How does latent TB survives in cells?
Cells stay dormant either inside macrophages or granulomas
Protect DNA
Ensure cell integrity (cell wall plays a role)
Lower metabolic activity and cells likely generate energy via a very low rate of respiration
Dormant cells are resistant to many TB drugs
How can latent TB be confirmed?
Person is infected with M-TB but does not have TB
Very big area of research
Can be detected with the Mantoux tuberculin skin test
What is an overview of first TB vaccine?
The Bacillus Calmette-Guerin vaccine was first used in 1921
An attenuated Mycobacterium bovis that was subcultured 239 times over 13 years
Shows clear protection in children
May protect against other respiratory illnesses in children
20-80% protective effect against leprosy
What is are problems with Bacillus Calmette-Guerin vaccine?
Efficacy in adults is debated
Differences between substrains
Genetic variation in populations
Exposure to environmental mycobacteria
Requires refrigeration
What is an overview of new TB vaccines?
No new vaccine approved
Many candidate vaccines in pipeline (phase3):
MTBVAC - Biofabri (Attenuated TB)
VPM1002 - SIIPL (Recombinant BCG)
Phase 2b - MVA85A - Oxford Uni (Viral vector-based TB)
What was the first effective drug treatment for TB?
First effective drug developed for TB was streptomycin
Isolated from Streptomyces griseus in 1943
Blocks the ribosome
First successful treatment in 1946
What is an overview of Isoniazid?
Targets mycolic acid biosynthesis, specifically InhA, the enoyl-acyl carrier
Must be activated by KatG
What is an overview of Pyrazinamide?
Converted by the M-TB enzyme pyrazinamidase to the active form
Inhibits coenzyme A biosynthesis
What is an overview of Ethambutol?
Targets enzymes involved in arabinogalactan and lipoarabinomannan biosynthesis
What is an overview of Rifampicin?
Inhibits RNA ploymerase
What is an overview of most TB antibotics?
ALL DRUGS HAVE SERIOUS SIDE EFFECTS
Isoniazid and Rifampicin are effective against latent TB
Most antibiotics only work against TB not other GP and GN bacteria and vice versa
Why do beta-lactams not work on TB?
Diffusion of beta lactam antibiotics (e.g. penicillin) are hundreds of fold slower than the penetration in E. coli and therefore are not effective
Why are M-TB resistant to macrolides?
M-TB are naturally resistant to macrolides (e.g. erythromycin) and lincosamides (e.g. lincomycin)
A protein called Erm7 limits affinity of these drugs to their targets in the ribosome
What other ways are M-TB resistant to antibiotics?
Chemical modification of drugs
Enzymatic degradation of drugs, e.g. Beta-lactamases
Drug export by efflux pumps
What is the typical treatment for TB using antibiotics?
The typical drug treatment is 2 antibiotics (isoniazid and rifampicin) for 6 months with 2 additional antibiotics (pyrazinamide and ethambutol) for the first 2 months of the 6-month treatment period(NHS)