Infection and Immunity Session Two: Host and Microbe Interactions
How do aminoglycosides prevent protein synthesis?
Once inside the bacterial cell, aminoglycosides bind to the 30s ribosomal subunit and cause a misreading of the genetic code. This leads to the interruption of normal bacterial protein synthesis
What are the actions of shigellae once invaded and inside the cell?
Once inside the cell, shigellae are surrounded by a membrane bound vesicle derived from the host cell The vesicle is lysed by the action into the cell cytoplasm. Once free in the cell cytoplasm, shigellae must multiply rapidly with subsequent inhibition of host cell protein synthesis. Several hours later the host cell dies, and bacteria spreas to adjacent cells, where the process of invasion is repeated
How do tetracyclines disrupt protein synthesis?
Once tetracyclines have been transported into the cell, this class of antibiotic reversible binds to receptors on the 30S ribosome subnit of the bacteria, preventing attachment of aminoacyl-tRNA to the RNA-Ribosome complex. This prevents the adition of amino acids to the elongating peptide chain, preventing synthesis of proteins
How do drugs that inhibit nucleic acid synthesis function?
Some antibiotics work by binding components involved in the process of DNA replication or RNA transcription, which causes interference of the normal cellular processes which will ultimately compromise bacterial multiplication and survival
What is meant by an endotoxin?
These are cell-associated substances. In a classic sense the term endotoxin refers to the to the lipopolysaccharide component of the outer membrane of gram negative bacteria. However, endotoxins may also be released from growing bacterial cells and cells that are lysed as a result of effective host defense (e.g. lysozyme) or the activities of certain antibiotics e.g. penecillins and cephalosporins When it is part of the microbrial structure itself
What is cholera caused by?
The enterotoxin Vibrio cholerae
What is a toxin?
These are chemicals produced by pathogens that either harm tissues or trigger host immune responses that cause damage
What are broad spectrum antibacterials?
These are active against both Gram negative and positive organsism
What is meat by broad-spectrum antibiotics?
These are drugs that have a wide antimicrobial scope e.g. tetracycline and chloramphenicol
What is meant by bacteriostatic antibacterial agents?
These are drugs that inhibit or delay bacterial growth and replication. The viable and total cell count remains the same. Halts the infection only
What are bacteriolytic drugs?
These are drugs that kill cells and lyse the bacteria, reducing both the viable cell count and the total cell count
What is meant by a narrow spectrum antibiotic?
These are drugs that only act on one kind or one strain of bacteria e.g. isoniazid for TB
What are type II exotoxins?
These are exotoxins that disrupt the membrane
Describe the action of type III exotoxins
These are intracellular effector toxins that translocate an active enzymatic component into the cell and modify an intracellular target molcule
Describe the action of type II exotoxins
These are membrane damaging toxins that directly affect membranes, forming pores or disrupting lipid bilayers
What is meant by bacteriocidal drugs?
These are antibacterial agents that kill target organisms, reducing the viable cell count but the total cell count remains the same. It is up to the body's immune system to lyse the bacteria
What is an antitoxin?
These are antibodies used against a specific toxin
Why are drugs used that inhibit metabolism (antimetabolites)?
They act on selected cellular processes essential for the survival of bacteria pathogen. These can be a metabolic pathway within the cell that are not essential for eukaryotic cells.
What is the function of adhesin proteins?
They allow the bacteria to adhere to mammalian cells where they bind to endothelial receptors. They also bind to proteins in the complement cascade allowing the surveillance system to be knocked out.
Why are antibiotics naturally occurring?
They are metabolic products of bacteria and fungi which have developed these to reduce competition for nutrients and space against other microbes
What type of bacteria is Vibrio cholerae?
A motile gram-negative, rod shaped bacteria with a small bend in the middle and a polar flagella
Give four examples of inhibitors of protein synthesis
Aminoglycosides: - Streptomycin - Neomycin - Gentamycin Tetracyclines Macrolides - Erythromycin Cholarmphenicol
How is cholera treated?
As there is water and electrolyte loss which are the main cause of cholera symptoms, water and electrolytes must be replaced as effectively as possible Oral replacement therapy is now the standard treatment. WHO only recommends antibiotics in severe cases
Give an example of a drug that combines penicliin with beta-lactamase inhibitors
Augmentin: Combines amoxicillin with clavulanic acid which inhibits penicllinase
Why are antimetabolites used that prevent mycolic acid synthesis or incorporation?
Because they inhibt synthesis of the mycobacterium cell wall (and hence only works on these bacteroa)
Why are antimicrobial drugs classed as a form of chemotherapy?
Chemotherapy are chemical based treatment for diseases caused by bacteria, other microorganisms, parasites and tumour cells. Hence it is not only for cancer, but anything chemical based, which antimicrobial agents are, are classed as this
What happens if cholera is left untreated?
Cholera will cause death in approximately 48 hours in 55% of cases
What is the advantage of invasion for pathogens?
Confers the ability to avoid humoral host defence mechanisms and potentially provides a niche rich in nutrients and devoid of competition from other bacteria
What are the four types of tetanus?
Generalised tetanus - Affects all skeletal muscles (most common) Local tetanus - Muscle spasms at or near the wound that has been infected with the bacteria Cephalic tetanus - Affects one or several muscles in the face rapidly after a head injury or ear infection. Trismus (locked jaw) may occur. The disease can easily progress to generalised tetanus. Neonatal tetanus - Affects a baby that is less than one month old
What are the effects of lipid A?
Induces effects such as: - Fever - Inflammation - Diarrhoea - Shock - Blood coagulation This can cause anaphylaxis even if it is present in a small amount.
What are the most important sources of infections?
Infected persons and carriers
What is the difference between colonisation and infection?
Infection - Germs are in our body and makes us sick Colonisation - Germs are in our body but do not make us sick
How are infectious disease transmitted?
Infectious diseases are transmitted from one host or reservoir to another, which can be done through contact, vehicle or vector
What happens if a V. cholerae bacterium survives the high acidic environment of the stomach?
It will stick to the walls of the small intestine and reproduce
What are bacterial capsules and describe their adavantages
Many bacterial pathogens have an extracellular polysaccharide capsule composed of sugar monomers that reduce the efficiency of host defences.
What is Siderophore?
Many bacterial pathogens have deceloped Siderophore which is a low molecular weight iron binding molecules
What must the microorganism do once it gains access to a tissue to produce disease?
Once a microorganism gains access to a tissue it must multiply to produce a disease
What happens once the microorganism has adhered?
Once adhered the bacteria induce intracellular signalling pathways that cause structural and functional changes in mucosal cells, and these may contribute to disease
Describe how bacteria release collagenase to help with the invasion into the host
Once bacteria attaches to the host cell's epithelial surface bacteria produce the enzyme hyaluronidase. This then releases collagenase that breaks down the collagen that allows the bacteria to invade deeper into tissues
Normally, how are the bacteria destroyed when phagocytosed?
When the phagosome is fused with the lysosome and exposed to lysosomal agents
Define pathogen
An organism that causes damage to the host
Define parasite
An organism that lives on or in a secondary organism called a host
What is meant by LD50? Why is it useful regarding classifying pathogens?
"Lethal Dose 50" It is the amount of the substance required to kill 50% of the test population It is used as an indication of virulence in pathogens
Give four examples of bactericidal agents
- Aminoglycosides - Cephalosporins - Penicllins - Quinolones
What are the three modes of action for antibacterial agents?
- Bacteriostatic - Bacteriocidal - Bacteriolytic
What are the inhibitors of nucleic acid synthesis targets?
- Beta-subunit of bacterial RNA polymerase - DNA gyrase / topoisomerase
What are drugs that target DNA gyrase / topoisomerase used to treat?
- Broad spectrum, bactericidal - Urinary tract infections - Respiratory infections
Give four examples of Clostridia:
- C. perfringens - C. difficile - C. tetani - C. botulinum
What is meant by facultative microorganisms?
- Can use oxygen - Can survive without oxygen
What is meant by obligate microorganisms?
- Cannot use oxygen - Damaged by oxygen
What is meant by aerotolerant microorganisms?
- Cannot use oxygen - Not damaged by oxygen
Describe the chain of the spread of infection
- Causative agent (pathogenic organism) - Reservoir / source - Means of exit: Way out of the body - Mode of transmission: Method of spread - Portal of entry: Way into the body - Person at risk
What are the direct effects of pathogens on host cells?
- Cell rupture - Organ blockage - Pressure effects
Give two examples of these enzymes
- Coagulase - Haemolysin
What does severe fluid and electrolyte loss result in because of the cholera toxin?
- Dehydration - Thirst - Metabolic acidosis due to loss of bicarbonate ions - Muscle cramps due to the loss of potassium - Sunken eyes and flaccid skin - Convulsions and coma in young children - Tachycardia - Hypokalaemia and hypovolaemic shock
Following exposure and infection the disease process can occur, this process is normally broken down into 5 stages. State these stages:
- Incubation period - Prodormal phase - Invasive phase - Decline phase - Concalescence period
What is the function of enzymes that are secreted by pathogens to invade host cells?
- Dissolve structural chemicals in the body - Maintain an infection - Invade further - Avoid body defences
What are the clinical features of Staphylococcal scalded skin syndrome (SSSS)?
- Exfoliation toxin - Bullae and skin exfoliation - Fever - Redness and lesions - Skin wrinkles and blisters - Skin exfoliation - Raw skin recovers
What are the symptoms of all three forms of the disease?
- Flaccid paralysis - Muscle weakness - Respiratory arrest
What are the three forms of disease that Clostridium botulinum toxins causes?
- Food borne Botulism - Infant botulism, where due to the infant intestinal environment if spores are ingestion with food the spores can proliferate and produce toxins - Wound botulism where there is an infection of the wound with Cl. Botulinum
List two drugs that work by hindering mycolic acid synthesis or incorporation
- Isoniazid (INH) - Ethambutol Both used to treat TB
What type of bacteria is clostridia?
- Large - Gram positive - Bacilli - Spore forming
What other extracellular enzymes are produced by bacteria?
- Mucinases - Phospholipases - Elastases - Collagenases - Hyaluronidases
By what routes of administration are antibiotics given?
- Orally - Intramuscularly - Intravenously
How do antihelminitcs act?
- Paralysing the parasite - Damaging worm leading to elimination by immune mechanisms - Interfere with metabolism of the worm
Give examples of drugs that target DNA gyrase / topoisomerase to inhibit nucleic acid synthesis
- Quinolones - Fluoroquinolones
Give examples of drugs that target the beta subunit of bacterial RNA polymerase
- Rifamycins - Anti-tuberculosis
What are the characteristics of the ideal antimicrobial drug
- Selectively toxic to the microbe but non-toxic to host cells - Microbicidal rather than microbistatic - Relatively soluble, functions even when highly diluted in body fluids - Remains potent long enough to act and is not broken down or excreted prematurely - Doesn't lead to the development of antimicrobial resistance - Complements or assists the activities of host defences - Remains active in tissues and body fluids - Readily delivered to the site of infection - Reasonably priced - Does not disrupt the host's health by causing allergies or predisposing the host to other infections
How do exotoxins cause damage or dysfunction?
- Signalling at host membranes (type I) - By damaging cell membranes (type II) - By entering target cells and directly altering function (type III)
When can infectious diseases occur depending on their time and place of occurence
- Sporadically - Epidemics - Pandemics - Endemic forms (regularly found among particular people or in a certain place)
What conditions does clostridia need?
- Strictly anaerobic - Fermentative
What are the three ways in which antibiotics are classified?
- Structure: Molecular structure - Spectrum of activity (what microbes they target) - Function of Mechanism of Action: How the drug works
Name two examples of antimetabolites that target folic acid synthesis
- Sulphonamides - Trimethoprim Sulphonamides target and bind to dihydropteroate synthase, trimethoprim inhibit dihydrofolate reductase. Both of these enzymes are essential in the production of folic acid, a vitamin synthesised by bacteria, but not humans
Give three examples of bacteriostatic agents
- Tetracyclines - Sulfonamides - Macrolides
What are the three most common side effects with antimicrobial drugs?
- Toxicity - Allergies - Changes to normal flora
What are the sites of entries in humans?
- Urogenital tract - Digestive tract - Respiratory tract - Conjunctiva
When looking at the generalised infectious cycle, where can infectious diseases be prevented?
1) A host is infected by the reservoir or a vector for the pathogen - Vaccines and drugs to prevent infection 2) An individual may infect other hosts in a population - Sanitation - Hygiene - Education 3) New vectors can arise - Vector control 4) The pathogen also may cycle between the vector and a reservoir
What are the two steps in the mechanisms of adherence?
1) Non-specific adherence 2) Specific adherence
What is the structure of Clostridium botulinum?
3-8 um long Thick Gram positive Sporing Can only be cultured anaerobically
Describe why antibacterials that inhibit protein synthesis are used
A constant supply of protein is essential for normal cell function. Prokaryotic ribosomes differ from eukaryotic ribosomes in both structure and size. By using drugs that target prokaryotic mitochondria you can have a selective product
Define lethality
A measure of how life-threatening an infection is
What type of toxin does Clostridium tetani release?
A-B Neurotoxin
What type of toxin is Cl. botulinum?
A-B neurotoxin
What toxins are exotoxins?
A-B toxins Cholera is an example
What mold forms Cephalosporins?
Acremonium cephalosporium
What are the 5 groups of potential bacterial contributors to the pathogenesis of infectious diseases
Adhesins Invasins Impedins Aggressins Modulins
What virulence factors help bacteria infect a host?
Adhesion to host cells (adhesins) Breaching of host anatomical barriers (invasins) and colonisation of tissues (aggressins) Strategies to overcome non-specific defences, especially antiphagocytic mechanisms Strategies to overcome specific immunity, the most important of which is production of IgA (impedins), molecular mimicry, and immunogen variability Damage to host tissues due to direct cytotoxicity Damage due to inflammatory reactions in the macroorganism - Attachment (via adhesins) - Colonisation (and eznymes) - Invasiveness - Toxins (and enzymes) - Inhibition of phagocytosis
What is the best course of action against cholera?
Although there are treatments available, the best course of action is preventing the spread of V. cholerae in the first place
What conditions can Vibrio cholerae survive in?
Always needs a source of water which can be: - Warm - pH more than 7 (basic) - Salty water It can survive in the human intestine making it a common contaminant of sewage
How may drugs alter the normal flora?
Antimicrobial treatment can cause opportunistic pathogens to cause secondary infections. Long term antibiotic growth of C. albicans and multiplication of C. difficile
What is the disadvantage of using drugs that target the disruption of cell membrane function
Because the structure is found in both eukaryotic and prokaryotic cells, the action of this class of antibiotic is often poorly selective and can often be toxic for systemic use in the mammalian host.
Describe why bacteria produce coagulase and kinase to help its invasion into host cells
Bacteria produce coagulase which allows the formation of a clot. This allows the bacteria to travel freely in the blood, protected from immune cells. Later, bacter produce kinase that allows the clot to dissolve and be released
How do A-B toxins functions?
Bacteria produces and releases exotoxin that binds to host receptors and the exotoxin enters the cell. An active component of the exotoxin alters cell function by inhibiting protein synthesis. B component is released from the cell
Hence, what mode of action do antimicrobials that inhibit cell wall synthesis adopt?
Bactericidal
What mode of action do inhibitors of protein synthesis tend to adopt?
Bacteriostatic Broad spectrum Can lead to toxicity problems
What mode of action do antimetabolites undertake?
Bacteriostatic action
Why is structure used for antibacterial classification?
Becaise antibiotics with a structural class usually show similar mode of action, spectrum of activity, and toxicity
Describe the mechanisms of action by which most antibacterial agents that disrupt protein synthesis act through
Bind to either 20S or 50s subunits of the intracellular ribosomes causing the disruption of the normal cellular metabolism of the bacteria, leading to the death of the organism or the inhibition of its growth and multiplication
Where can antivirals target?
Blocking of viral absorption and penetration of a virus into the host cell Blocking of the uncoating of a virus Blocking of early protein synthesis Blocking of nucleic acid synthesis Blocking of late protein synthesis and processes Blocking of packaging and assembling Blocking by neuraminidase inhibitors to prevent viral release
What bacteria release exotoxins?
Both gram positive and gram negative bacteria. All major gram positive bacteria produce exotoxin
Compare the cephalosporins to penicllins
Both have beta-lactam rings so resemble each other, however cephalosporins have a broader spectrum
How is cholera contracted?
By drinking water or eating foods contaminated with V. cholerae
How must control of infectious disease within a populace be supported?
By effective legislation that regulates mandatory reporting where required. Further measures must be implemented to prevent exposure, for example: - Isolation - Quarantine - Disinfection - Sterlisation - Use of insecticides - Dispositional prophylaxis (active and passive immunisation, chemoprophylaxis)
Describe the signs and symptoms associated with Toxic Shock Syndrome Toxin 1 (TSST-1)
Caused by a superantigen - Hypotension - Desquamative skin lesions - Organ dysfunction
Why are drugs used that disrupt cell membrane function?
Cell membranes are important barriers that segregate and regulate the intra and extracellular flow of substances. A disruption or damage to this structure could result in leakage of important solutes essential for the cell's survival
Give an example of a type II exotoxin
Clostridium - Causes gas gangrene
What organism does the Botulinum toxin come from?
Clostridium botulinum
What pathogen releases the tetanus toxin?
Clostridium tetani
What is the first stage of microbial infection?
Colonisation - The establishment of the pathogen at the appropriate portal of entry
What is polymxin B combined with when given as a treatment?
Combined with bacitracin and neomycin (broad spectrum)
What bacteria release the endotoxin lipid A?
Dead gram negative bacteria
How can some antibiotics be both bacteriostatic and bactericidal?
Depends on their dose, duration or exposure, and state of the invading bacteria
What do most organisms who infect sites of entries in humans have?
Developed tissue adherence mechanisms and ability to overcome the host defences
What four ways are used to determine microbial sensitivities (how well a drug acts on a specific microbe)
Disk diffusion method - Disc contains a certain concentration of antibiotic. Shows the effectiveness of the antibiotic in stopping the growth Dilution method - Increasing dilute concentrations of the antibiotic are used with the bacterial cultural to see what concentration the growth is stopped Serum killing power Automated methods
Compare the immunogenecity of exotoxins and endotoxins
Exotoxins: Highly immunogenic. Stimulates the production of neutralising antibodies (antitoxin) Endotoxins: Relatively poor immunogen. Immune response not sufficient to neutralise toxin
Why have antivirals become more important?
Due to the setting of immunosuppresion - both drug induced and AIDS
Give an example of a zoonotic pathogen
E.Coli
Compare the mode of action and symptoms of exotoxins and endotoxins
Exotoxins: Specific. Either cyotoxin, enterotoxin, or neurotoxin with defined specific action on cells or tissues Endotoxins: General: - Fever - Diarrhoea - Vomiting
Why is oral administration the most preferred method?
Easiest, patients can do it themselves. Also for many drugs oral administration results in therapeutic blood levels to rise as nearly as rapidly as IV administration
Describe Paiul Ehlrich's contribution to medication
Ehrlich proposed to use chemicals to selectively kill pathogens while having no effect on the patient. This is the concept of selective toxicity, where drugs specifically target microbial processes, and not the human host cellular processes. He termed this chemotherapy. He had a vision of finding the "magic bullet". He had success developing an arsenic based drug for syphilis
How are pathogens transmitted from these sources to susceptible persons?
Either directly (person to person) or indirectly via inert objects or biological vectors.
What do endotoxins do that exotoxins don;t?
Elicit immune response mechanisms
What are the two types of toxins that a bacteria can produce?
Endotoxin Exotoxin
Exotoxins or endotoxins are a common cause of serious tissue damage?
Exotoxins
Define enterotoxin
Exotoxins that act on the small intestine generally causing massive secretion of fluid into the intestinal lumen
Compare the fever potential in both exotoxins and endotoxins
Exotoxins: - Do not produce fever in host Endotoxins - Pyrogenic, often produce a fever in host
Compare the chemical properties of exotoxins and endotoxins
Exotoxins: These are proteins excreted by certain gram positive or negative bacteria, which are generally heat labile (liable to change) Exotoxins: Lipopolysaccharide-lipoprotein complexes released on cell lysis as part of the outer membrane of gram negative bacteria. These are extremely heat stable
Compare the toxoid potential in exotoxins and endotoxins
Exotoxins: Treatment of toxin with formaldehyde will destroy toxicity, but treated toxin (toxoid) remains immunogenic Endotoxins: None
What is another term for pili?
Fimbriae
What toxins may damage or destroy cells?
Heamolysins
Why do animal bodies provide favourable environment for the growth of microorganisms?
Host bodies provide organic nutrients and growth factors, constant conditions of temperature, pH and osmotic pressure.
Define mortality
How many deaths are caused by a given disease in a given population
What is the advantage of using drugs that inhibit cell wall synthesis?
Human cells do not have cell walls but it is critical for the life and survival of bacterial species. A drug that targets cell walls can therefore selectively kill or inhibit bacterial organisms. This means they have a low toxicity to humans
When does the presence of these microorganisms become a diseased state?
If they are found in significant quantities in organs, blood or lymph system
How do antifungals act?
In a similar way to antimicrobials where drugs inhibit nucleic acid synthesis
Where are microorganisms usually found in host bodies?
In regions that are exposed to the outside environment
Where is C.tetani found?
In spores in soil or in the GI tract in animals
When is IV administration preferred?
In the following circumstances: - Oral antibiotics cannot be tolerated (e.g. because of vomiting) - Oral antibiotics cannot be absorbed (e.g. because of malabsorption after intestinal surgery - Intestinal motility is impaired (e.g. because of opioid use) - No oral formulation is available - Patients are critically ill, possibly impairing GI perfusion or making even the brief delay with oral administration detrimental
What are the 5 main mechanisms of action of antibacterials?
Inhibition of cell wall synthesis Inhibition of protein synthesis Inhibition of nucleic acid synthesis Disruption of cell membrane function Inhibition of metabolism (antimetabolites) not used by in humans ---------------------------------------------------- Others: Drugs that block a pathogen recognition of or attachment to its host
How do protease inhibitors act as antimetabolites?
Interfere with the action of protease as an enzyme used by HIV during its replication cycles
What type of bacteria is neuraminidase released from?
Intestinal pathogens
What are invasins as virulence factors?
Invasins are proteins (enzymes) that act locally to damage host cells and / or have the immediate effect of facilitating the growth and spread of the pathogen
What process happens after adhesion (only in some organisms)?
Invasion
After colonisation, how does the bacteria proceed?
It invades and enters the cell, to make us feel ill
What is the name and type of the cholera toxin?
It is called the cholera toxin, which is an A-B toxin with one A subunit and 5 B subunits
Within the context of medical microbiology, what is meant by the study of epidemiology?
It is the study of occurrence, causality, and prevention of infectious diseases in the populace
State how Streptococcus pyogenes achieves antiphagocytic factors
It produces an M protein that increases virulence.
How many toxins does Clostridium botulinum form that have been found to be harmful to humans?
It produces many toxins, of which 4 are harmful to humans - A, B, E, and F
Therefore, when are drugs that target cell membrane function used?
Limited to topical applications e.g. polymyxin B (gram negatives) that are used to treat skin infections
Define endotoxin
Lipopolysaccharides that are present on the outer layer of gram negative cell walls
Give an examples of a disease that produces IgA proteases
Meningitis
What type of bacteria can drugs that target the beta subunit of bacterial RNA polymerase can act on?
Narrow spectrum - Mycobacteria / Gram positives
What are the advantages of semisynthetic penicillins over natural penicillins?
Natural penicllins have a narrow range of activity, so they are modified to enhance activity. For example peniclinase-resistant penicillins are used to combat drugs that have developed resistance by making beta lactamase. For example methicillin that is used for MRSA
What are the three classes of toxins?
Neurotoxin - Acts on the nervous system Enterotoxin - Acts on the gut Superantigens
Is pili present in all bacteria?
No
Between 1962 and 2000, no major classes of antibiotics were introduced. What was the problem with this innovation gap?
No new drugs were coming forward so drugs were starting to lose their effectiveness with bacteria becoming resistant. Antimicrobial stewardship is to not over prescribe drugs when they are not needed
What host defence mechanisms confront bacterial pathogenicity factors?
Non-specific defences including mechanical, humoral, and cellular systems Phagocytosis Specific immune responses based on antibodies and specific reactions of T lymphocytes
Describe the action of the cholera toxin
One of the B subunits binds to a glycoprotein receptor of the cytoplasmic membrane of the intestinal epithelial resulting in cleavage of the A subunit The part A enter the cell cytoplasm and activates adenylate cyclase Adenylate cyclase converts ATP to cAMP cAMP stimulates active secretion of electrolytes (mainly sodium ions) from the cell into the intestinal lumen Water typically flows towards the highest concentration of electrolytes, so copious amounts of water enter the intestine. This is rice-water stool and is the hallmark of cholera Main result watery diarrhoea
What are the disadvantages of bacteriostatic drugs over bacterocidal and bacterolytic?
Onset of bacteriostatic drugs agents are generally slower than that of bactericidal agents. Bacteriostatic drugs require a working immune system for effective elimination of the microorganism by the infected host. Bacteriostatic antibiotics are therefore not advisable for use in immunosuppressed or immunocompromised conditions and those suffering from life-threatening acute infections.
What blood borne virus is the antigenic variation highly developed in?
Parasitic protozoa such as trypanosomes
Name four classes of antibiotics that are beta lactam antibiotics
Penicillins (1) Caphalosporins (2) Bacitracin Vencomycin
What mold produced penicillins?
Penicllium chrysogenum
Defective defences make it easier for an infection to take hold. What type of defects are the least and most common?
Primary, innate defects are rare, whereas acquired, secondary immune defects occur frequently, having the way for infections by microorganisms known as facultative pathogens (opportunistic pathogens)
Define incidence
Rate occurrence of new cases
Define infection
Refers to the growth of microorganism in a host, it is not synonymous with disease
What is meant by specific adherence?
Reversible permanent attachment of the microorganism to the surface (sometimes called anchoring)
What is the function of immunoglobulin A proteases?
Several species of pathogenic bacteria that cause disease on mucosal surfaces produce a proteases that specifically cleaves the principal antibody type produced at these sites, IgA
Describe the invasion of shigellae
Shigellae invade the colonic mucosal cells but rarely penetrate deeper into the host tissues.
What disease does shigellae cause?
Shigellosis that leads to dysentery
Describe how some drugs block a pathogens recognition of or attachment to its host
Some new antimicrobial agents block the attachment of microbes, especially viruses, to the host cells using attachment analogues. Using peptide and sugar analogues the viruses can neither attach nor enter a cell
However, describe how some pathogens are able to combat this
Some pathogens can survive within macrophages and other phagocytes and can multiply intracellularly. For example M. tuberculosis is thought to resist intracellular killing by preventing phagosome-lysosome fusion, other bacteria are able to resist the action of such lysosomal components after fusion
What is the main cause of Toxic Shock Syndrome Toxin I?
Tampons inserted that are not changed regularly as they should. Creates a breeding environment for bacteria
How does the M protein present on the surface of S. pyogenes different to this?
The M protein present on the surface of the S pyrogenes is not a capulse but functions in a similiar manner
Define pathogenicity
The ability of a microorganism to cause disease
How can bacteria cause indirect damage due to inflammatory reactions?
The activation of complement and phagocytosis Induction of cytokine production (modulins)
How do pili or adhesions change depending on the host?
The adhesins or pili will change slightly to bind to the receptor on the cell type they are going to infect
What happens after the adhesion of the bacteria?
There is colonisation where multiple bacteria surround the host cell
What does virulence depend on?
The composition of the genome.
How is Siderophore used in bacterial pathogens?
The concentration of free iron in body fluids and secretions is below that required for bacterial growth because it is bound by transferrins and lactoferrin. So bacterial Siderophore is a low molecular weight iron-binding molecules that transport Fe3+ actively into the intracellular space. The siderophore complex with iron, thereby stealing this element from proteins containing iron
Define virulence
The degree of pathogenicity
What are the three ways in which bacterial capsules aid defence against host mechanisms
The hydrophilic nature of the capsule may hinder uptake by phagocytes. This may be overcome if the phagocyte is able to trap the bacterium against a surface, a process referred to as surface phagocytosis Capsules prevent efficient opsonisation of the bacterium by complement or specific antibody, reducing interaction with phagocytic cells Capsules are weakly immunogenic. In some cases the capsular polysaccharide may mimic host polysaccharides moieties and be seen as a self-antigen
Define infection
The invasion of a pathogen
What do we need to know in order to select the most antimicrobial agent?
The organisms's identity Gram negative or positive The organism's susceptibility to a particular agent The site of infection - blood brain barrier effects, protein binding, lipid solubility and MW of the drug Patient factors: - Renal / hepatic nature - Age - Sex - Pregnancy The safety of the agent The cost of therapy
Why are antimicrobrials that function to inhibit cell wall synthesis more effective on Gram positive bacteria than Gram negative?
The peptidoglycans in Gram positive bacteria are more accessible, as they are not sandwiched between two layers of memebrane
Define prevalence
The proportion of cases in a population at a given time
What does host-pathogen interaction depend on?
The rate of adaptive response How much the pathogen adapts to the environment to achieve stability On how well the immune system works depends what immune state the person will be in - It is uncommon for a microbe to cause exactly the same disease in all infected individuals - Host Defences vs Immune Evasion by Microbes
What are opportunistic pathogens?
These are pathogens that are part of the normal flora, that may be carried on the skin or mucosal surface of the body. Under normal conditions opportunistic bacteria cause no harm and may actually have a beneficial effect by preventing colonisation by other potential pathogens. However, when these bacteria are introduced into anatomical sites where they are not normally found, or competing bacteria are removed by the use of broad spectrum antibiotics, these normally harmless bacteria may multiply locally and lead to the development of disease
What is meant by an exotoxin?
These are released from bacterial cells and may act at tissue sites removed from the site of bacterial growth Something that is produced in the bacteria and leaves the microorganism
Why are retroviruses specifically targeted by anti-retrovirals
These are retro viruses that have a RNA genome. They have an extra step not present in human cells, where they have reverse transcriptase to convert RNA genome into the DNA genome that is needed for replication. Hence anti-retrovirals can use nucleoside reverse transcriptase inhibitors (NRTIs) Protease inhibitors can be used, where protases are used to break down translated polypeptides. This means the virus is left with the long polypeptide that can't be functional Fusion inihibitors
What are modulins?
These are substances that induce excess cytokine production i.e. lipopolysaccharide of gram-negative bacteria, superantigens, murein fragments
What are impedins?
These components disable host immune defences in some cases
How do drugs that target DNA gyrase / topoisomerase function?
These enzymes function in bacteria to unravel DNA needed for the DNA replication. It interferes with separation / reannealing of dsDNA to prevent protein synthesis
What are narrow spectrum antibacterials?
These have a limited activity and are primarily only useful against particular species of microorganisms
What is the function of extracellular enzymes secreted by bacteria?
These increase the pathogenic processes
Describe atovaquone has an antimetabolite
These interfere with electron transport in fungi and protozoa, while heavy metal inactivate enzymes
Describe the advantages of drugs that target the metabolic pathway of folic acid synthesis
These prevent the synthesis of folic acid required for synthesis of purines and nucleic acids. It does not affect human cells which can use preformed folic acid
Describe Staphylococcus aureus's antiphagocytic factors
These produce an invasion called leukocidins, a chemical capable of destroying phagocytic white blood cells
What is the function of antiphagocytic factors that some bacteria produce?
These produce chemicals that prevent the fusion of the lysosome with phagocytic vesicles, so the bacteria can survive within the cells
What needs to be considered when selecting an antimicrobial for use?
These require clinical judgement, detailed knowledge of the pharmacological and microbiological factors Empirical therapy - initial = infecting organism not identified - single broad spectrum agent Definitive therapy - microorganisms identified - a narrow spectrum low toxicity regiment to complete the course of treatment
What are aggressins?
These substances include toxins and tissue-damaging enzymes
What are the functions of antimicrobial agents?
They are products used to control microorganisms in commercial and industrial application e.g. - Chemicals in foods - Air conditioning cooling towers - Textile - Paper products - Fuel tanks Products designed to prevent the growth of human pathogens in inanimate environments and on external body surfaces - Sterilants - Disinfectants - Sanitisers - Antiseptics Antimicrobial drugs - Chemotherapy
What are invasins?
They are responsible for the active invasion of the cells of the microorganism
What is the result of superantigens?
They cause an immune response due to the release of cytokines from host cells to cause: - Fever - Nausea - Vomiting - Diarrhoea - Shock - Death This is toxic shock syndrome
What are adhesins?
They facilitate adhesion to specific target cells
How do chloramphenicols disrupt protein synthesis?
They irreversibly bind to the receptor site on the 50S subunit of the bacterial ribosome, inihibitng peptidyl transferase. This inhibition consequently results in the prevention of amino acid transfer to growing peptide chains, ultimately leading to inhibition of protein formation
How do type II exotoxins lyse host cells?
They make protein channels in the plasma membrane (e.g. leukocidins, haemolysins) that disrupt the phospholipid bilayer
How does Vibrio cholerae move?
They swim quickly in infected water using their flagella in a whip-like manner to propel forward
How do beta-lactam rings function?
They target penicillin-binding proteins (PBPs), a group of enzymes found anchored on the cell membrane, which are involved in the cross linking of the bacterial cell wall. The beta lactam ring portion of this group of antibiotics binds to these different PBPs. rendering them unable to perform their role in cell wall synthesis. This leads to the death of the bacterial cell due to osmotic instability or autolysis.
Describe polymyxin B has a drug
This disrupts the cytoplasmic membrane causing leakage and death. Peptide derivatives One end of the molecule is water soluble and the other end is hydrophob - Topical - Bactericidal - Gram negative
Define pathogenesis of bacterial infection
This includes the initiation of the infectious process and the mechanisms leading to the development of signs and symptoms of bacterial disease
Describe the process of non-specific adherence
This involves attractive forces (hydrophobic interactions, electrostatic attractions, atomic and molecular vibrations resutling from fluctuating dipoles of similar frequencies, Brownian movement, recruitment and trapping by biofilm polymers interacting with the bacterial glycocalyx capsule)) that allow bacterium to come in contact with eukaryotic cells
What are adherence blockers?
This is a defence mechanism on eukaryotic cells that prevents adhesins on bacteria from joining into them
What type of bacteria is Clostridium tetani?
This is a gram positive rod-shaped anaerobic species of the genus Clostridium
What are beta lactam antibiotics?
This is a group of compounds characterised by its four membered, nitrogen containing beta lactam ring at the core of its structure, which is the key to the mode of action of this group of antibiotics.
Describe pili as a virulence factor
This is a hair-like appendage found on the surface of many bacteria. These attach to host cells and sometimes help with motility
What is an antibiotic?
This is a low-molecular substance produced by a microorganism (natural) that at low concentrations inhibits of kills other microorganisms, All antibiotics are antimicrobials, but not all antimicrobials are antibiotics
Describe the functions of neuraminidase
This is an enzyme present in many pathogenic or symbiotic microorganisms, which catalyses the breakdown of glycosides containing neuramic acid which is the predominant sialic acid found in mammalian cells
What is meant by toxoid?
This is an inactivated toxin used in a vaccine
What is an antimicrobial?
This is any substance of natural, semisynthetic or synthetic origin that kills or inhibits the growth of microorganisms but causes little or no damage to the host.
What type of bacteria is shigellae?
This is gram negative, facultative aerobic rod bacteria
What is non-specific adherence?
This is reversible attachment of the bacterium to the eukaryotic surface (sometimes called docking)
Define toxigenesis
This is the ability to produce toxins.
Define the therapeutic index
This is the dose of a drug a patient can take proportional to the drug's effective dose
What are virulence factors?
This is the name given to a variety of traits that interact with a host and enable the pathogen to enter a host, adhere to the cells, gain nutrients and evade the immune system. - Invade the host - Evade host defences - Cause disease
What is meant by toxaemia?
This is the presence of a toxin in the host's blood
Define therapeutic range
This is the range of concentrations of the drug that are effective without being toxic
What is meant by antimicrobial spectrum of activity?
This is the scope that a drug kills or suppresses the growth of microorganisms
What is invasion?
This is when organisms invade either the mucosal cells or penetrate deeper into the tissues.
What is the advantage of antigenic variation during the course of infection?
This provides a mechanism of avoidance of specific immune responses directed at these antigens.
Describe what happens when drugs target the beta subunit of bacterial RNA polymerase
This stops RNA synthesis and the transcription of genes - stops the bacteria from producing proteins
Describe the mechanism of action of drugs that inhibit cell wall synthesis
To enlarge or divide a cell, the bacteria must synthesise peptidoglycan by adding N-acetylglucosamine and N-acetylmuramic acid. These drugs target the peptidoglycans in the cell wall to prevent the cross linking of N-acetylmuramic acid (NAM) subunits This causes weakening of the cell wall while the cell is growing causing the death of the bacteria. This also makes the bacteria more susceptible to the environment, where it will lead to water uptake in a hypertonic environment leading to cell lysis as the bacteria bursts
Why are penicillins sometimes used alongside beta-lactamase inhibitors?
To inhibit beta lactamase so the penicillin doesn't get broken down by bacteria that have developed this aspect of microbial resistance, where they can break open the beta-lactam ring to make penicillin not functional
Define exotoxin
Toxins released extracellularly as the organism grows
Describe the actions of type I exotoxins
Type I exotoxins are membrane acting. They bind to surface receptors and stimulate transmembrane signals, and include super-antigenic toxins
What type of toxin are superantigens?
Type I toxins
What type of toxins are A-B exotoxins?
Type III toxins - Inteacellular effector. Toxins translocate an active enzymatic component into the cell and modify an intracellular target molecule
What extracellular enzymes does Proteus spp produce?
Ureases that break down urea in the urine, and the release of ammonia may contribute to pathology
What condition does Proteus spp cause?
Urinary tract infections
Why are antiviral chemotherapies less developed than antmicrobials?
Viruses are more difficult targets than bacteria because even though they are msot vulberable during reproduction they: - All use host cells organelles to do this - Antiviral compounds are often as toxic to the host as the virus
Describe the pathogenesis behind the Cl. Botulinum when ingested
When Cl. botulinum or their toxins are ingested in food the toxins are absorbed into the bloodstream until they reach the peripheral nervous system. The metalloprotease toxin catalyses the proteolysis of key proteins so they block neurotransmission, inhibits ACh release, resulting in flacid paralysis. Death usually results from resporatory paralysis
Define attenuation
When a pathogen's virulence is reduced e.g. in cultured conditions
When does tetanus most likely occur?
When a wound becomes contaminated with Clostridium tetani bacterial spores
Why are newer generations of cephalosporins advantageous over older generations?
When developed again it becomes the second generation, which is then developed further and becomes the third generation etc. Newer generations are less susceptible to beta-lactamases
Describe the process of specific adherence
When pathogenic bacteria come into contact with intact human surface tissues (e.g. mucosa), they adhere to receptors on the surface of the target cells using various surface structures of their own - Attachment pili - Attachment fimbrae - Adhesion proteins in the outer membrane of gram negative bacteria - Cell wall associated proteins gram positive bacteria There is a specific process that involves the formation of many specific lock and key bonds between complementary molecules on each cell surface
When do C.tetani produce disease?
When the spores become activated and develop into gram positive bacteria that multiply and produce the powerful toxin tetanospasmin. Tetanospasmin binds to motor nerves that control muscles, enter the axons, and travels in the axon until it reaches the body of the motor nerve in the spinal cord or brainstem. Then the toxin migrates into the synapse where it binds to nerve terminals and inhibits or stops the release of the inhibitory neurotransmittors glycine and and gamma-aminobutyric acid, causing the muscle to tighten up in huge continuous contraction or spasm. If tetanospasmin reaches the bloodstream or lymphatic vessels from the wound site, it can be deposited in many different locations and result in the same effect on other muscles
Where is Clostridium botulinum found?
Widespread in the soil and intestinal tract of many animals
What is meant by a zoonotic pathogen?
Zoonosis pathogen are found in a variety of animals and may be transferred to humans coming into contact with animals directly or indirectly
