elizabeth (L9-10) Flashcards
slow growth
E coli can get at least 3 doublings per hour - highest here
Even fast growing mycobacterium only have 1 doubling per hour
Different conditions for them to grow, so need an enclosed space where the air is filtered
Research is very difficult because of this
small colony variants
Drug resistance sub population
Antibiotic resistance helps them survive
Mucus layer of polysaccharide allows it to grow over it
Staphylococcus are fast growing usually
They colonise somewhere like knee or joints (they form a biofilm and mutate, cause auxotrophy) they can still grow because they utilise dead cells and bacteria
Slow growing so very difficult to kill with antibiotics
(Columbia blood-agar plates that show the normal and the small colony variant phenotype of Staphylococcus aureus Implicated in nosocomial infections)
Antibiotics for treating infections with SCVs
antibiotics target processes required for growth; the biosynthesis of proteins, peptidoglycan, folic acid, DNA and RNA.
Biofilm-mediated infections and tuberculosis (TB) – unmet clinical need owing to bacteria that are either slow growing or dormant and therefore hard to treat
Once they are quiescent, their antibiotic resistance increases and are difficult to treat
Biofilm-mediated infections
Biofilm-mediated infections range from those
involving medical-device implants, including
bloodline catheters and heart implants, to
those associated with cystic fibrosis, wounds
and superficial skin infections
TB
TB is the most devastating bacterial infection of humans, causing ~2 million deaths per year. It is estimated that one-third of the world’s population is infected with asymptomatic, dormant M. tuberculosis, from which new cases of active infection arise (~8 million annually)
Antibiotics active against dormant bacteria
DAPTOMYCIN - used to treat cSSSI (complicated skin and skin structure infections)
MYCOBACTERIA DRUGS - to treat tuberculosis, drugs like CLOFAMIZINE, BEDAQUILINE, PRETOMANID
define ionophores
a substance which is able to transport particular ions across a lipid membrane in a cell.
chemical structures of various membrane -active agents Molecules that perturb the membrane vary greatly in size and chemical structure
these factors influence
the sum of the
interactions made in the complex membrane
environment, define
how rapidly these compounds act and determine whether they are bactericidal
common feature of all membrane-active agents
common feature of all membrane-active agents is their high lipophilic content, which enables them to interact with the hydrophobic
membrane.
With the exception of clofazimine, which kills latent mycobacteria, these compounds all have reported
anti-biofilm properties.
The intracellular parasite/pathogen
An intracellular location provides a survival niche for bacteria, because the micro- organisms are protected against antibiotic therapy and host defences.
S. AUREUS
S. aureus is not only an extracellular pathogen but also an intracellular pathogen, owing to effective uptake of these bacteria by non-professional phagocytes, such as endothelial and epithelial cells, fibroblasts, osteoblasts and keratinocytes.
SCV
svc internalisation is mediated by fibronectin bridging between the bacterial fibronectin-binding proteins (FnBPs)
and the receptor α5β1-integrin, which is present at the surface of eukaryotic cells
EXAMPLES S aureus Wolbachia bacteria Brucella M. tuberculosis
infection by intracellular parasites
they enter macrophages, stay there and are transmitted to other cells or form
Dendritic cells and macrophages are infected and infectious
They subvert the immune response of the macrophage. The phagosomes inside the cell cannot digest them. (all mycobacteria can do that)
Other bacteria have intracellular growth - need resistance to hypoxia because of the free radical production in the phagosome and hydrogen peroxide
Difficult to treat
Go into stages of latency
leprosy caused by?
a slow growing pathogen
Mycobacterium leprae causal agent of leprosy
Leprosy only develops if you have been living with lepers for a very long time (difficult to catch)
BCG is the TB vaccine and gives immunity to leprosy
facts about leprosy
Leprosy, (or Hansen’s Disease), is a chronic infectious disease of the skin
and nerves.
The causal agent is Mycobacterium leprae.
Symptoms are
loss of sensation in hands and feet, leading to disability through injury,
and blindness
not really contagious but caught via close contact over an extended period and is mainly spread through droplets from the nose and mouth by coughing and sneezing. Also via skin particles in dust within housing of infected individuals can be inhaled and transmit the infection so there is a potential environmental reservoir
(( Leprosy is one of the oldest and most stigmatised of diseases. The stigma attached to leprosy which can result in rejection and exclusion means there is widespread misunderstanding about the disease ))
treatment of leprosy
Leprosy is curable through Multidrug Therapy (MDT). MDT is a combination of two or three drugs, clofazimine, rifampicin and dapsone which are administered over two years. MDT combined with early diagnosis also prevents permanent disabilities by curing the disease before it causes deformities.
cultivation of lepri and its current endemics
Leprosy is a chronic granulomatous disease affecting the skin and peripheral nerves
Cultivation of lepri - difficult organism to treat, and to screen for a drug therapy
Usually drug therapy is done on a live organism
Despite its being the first identified pathogen in humans, leprosy remains endemic in central Africa, Southeast Asia and South America with more than 200,000 new cases per year globally. Our understanding of its pathogenesis and interaction with the human host is limited, in part due to the inability to culture the bacterium in vitro.
mycobacterial cell wall features
(extracellular environment) - capsule like material - MAPc: mycolic acids AG (arabinan and galactan) peptidoglycan - cell membrane (intracellular environment)
Unique cell wall - capsule like material of long chain fatty acids
20 carbon lengths, they are like candle wax
When cells grow, they aggregate together and makes it difficult to work with
Peptidoglycan is linked to mycolic acids with arabinogalactan polymers. The synthesis of these arabinogalactan polymers is a good target for drug therapy
ziehl neelsen stain
The ziehl neelsen stain was the first to use for diagnosis by staining a piece of skin (phenyl red will stain mycobacterial cell because of its impermeable membrane that will not allow the stain out)
The leprosy spectrum and possible mechanisms of tissue damage
LEARN DIAGRAMS IN L9 S14
Lepromatous leprosy is characterized by…?
Lepromatous leprosy is characterized by aTh2 T-cell immune response (interleukin-4 [IL-4] and IL-10), antibody complex formation, the absence of granulomas, and failure to restrain M. leprae growth. In lepromatous leprosy, robust antibody formation occurs but is not protective, and cell-mediated immunity is conspicuously absent
Tuberculoid leprosy is characterized by…?
tuberculoid leprosy features Th1 T-cell cytokine response (gamma interferon [IFN-] and IL-2), vigorous T-cell responses to M. leprae antigen, and containment of the infection in well-formed granulomas
M leprae
M. leprae is an obligate intracellular pathogen with a distinct tropism for Schwann cells of the peripheral nervous system and for macrophages
T helper cell 1 vs 2
If you establish a good defense, you can subvert the infection and the cellular base immunity will be able to deal with it
→ T helper cell 1 mediated resistance (tuberculoid pole)
If you have induction of T helper cell 2, then you are on the other end of the pole and you get a humoural response
Antibody response doesn’t work very well and they can’t bind to leprosy (because it is non immunogenic because of the wax) especially when it is intracellular
→ T helper cell 2 induction (leproid pole)
Tuberculoid pole
Tuberculoid pole - you get aggregation of macrophages and antibodies migrate there but are not effective
Cells spread out and reach the nerve cells
There’s a high attraction/tropism for schwann cells in the peripheral nervous system
Lose blood supply which gives numbness as the cells die and they digest their myelin sheaths (demyelination)
