Module 7 - Epidemology, antibiotics, and antibiotic resistance Flashcards
Epidemiology
To carry out disease surveillance; to describe, analyse & understand the spread of disease
Endemic
Constantly present - causes a low-level frequency of disease at regular intervals (colds, human flu, etc)
Epidemic
Sudden increase above the expected (chickenpox etc)
Pandemic
Increase simultaneously over a wide area (global) (AIDS, FLU, COVID-19, etc)
Epidemics/pandemics in plants
Also pose a significant threat to local and global food security, exacerbating the problem of malnutrition (maize lethal necrosis, rice tungro, sweet potato virus, banana bunchy top, citrus tristeza, plum pox)
Losses caused by plant viruses are thought to cost global agriculture approximately $30bn (£22bn) a year
Morbidity vs mortality rate
Morbidity - % of people who get it
Mortality - % of people who die due to it
Two types of epidemic
Common source epidemic - Sharp rise to a peak and rapid decline (ie food poisoning)
Propagated epidemic - Slow rise and gradual decline (ie chickenpox rising in summer, falling in winter)
Herd immunity: the definition and the effect on flu, polio, and the measles
Resistance of a population to infection - due to the immunity of the majority
Flu - 90% immunised - disease prevented
Polio - 70% immunised - less contagious
Measles - 90-95% immunised - disease prevented
Antigenic shift
Minor antigenic variation due to mutations may alter haemagglutinin, neuraminidase, or amino acid sequences which may invalidate vaccines
Types of epidemic control
Eliminate source - quarantine/destroy reservoir
Break connection between source and host
Raise the level of herd immunity - vaccination
Zika virus: where was it first discovered, when was it first discovered, what are its symptoms, and how is it transmitted?
First isolated in the Zika Forest in Uganda in 1947
No or mild symptoms but if transmission occurs in utero then brain defects may occur (microencephaly and severe brain malformations)
Transmission:
* (Aedes aegypti) mosquito
* Sexual transmission
* Blood transfusion
* Vertical transmission can occur in utero
Re-emergence of viruses: what are the ways it may occur and what examples are there?
1 - Demographics - move to cities (crowded)
2 - Transportation – bulk processing -> distribution -> speed of spread
3 - Economic development & changes in land use- eg build dam -> mosquitoes -> disease
4 - International travel (SARS/flu)
5 - Microbial adaptation (flu)
6 - Biological warfare (anthrax, plague, Ebola, botulinum toxin)
7 - breakdown of public health measures (cholera)
Antimicrobials: what is the idea and why is the idea slay?
Idea formulated by Paul Ehrlich - basically an antibiotic
Antibiotics: how do they work and what antibiotics are used to stop which process?
They have selective toxicity by targetting unique bacterial sites (prokaryotic cells):
- Cell wall synthesis inhibitors - penicillins (emphasis today)
- Protein synthesis inhibitors – aminoglycosides & macrolides
- Nucleic acid synthesis inhibitors – quinolones
- Folic acid biosynthesis- sulphonamides
Types of antimicrobial methods
Bacteriostatic - growth inhibited by ribosome synthesis inhibitors (treatment must go on long enough for the immune defence to destroy the pathogen as it is only prevented from growing, not killed)
Bactericidal - killing pathogens, this is the preferred method
Antimicrobials: cell wall synthesis inhibitors
Penicillin and cephalosporins
B-lactam antibiotics - they have a ß lactam ring (heterocycle ring with 3 carbons and a nitrogen) for activity which inhibits peptidoglycan biosynthesis
Penicillin: what was the first type of penicillin produced, how does penicillin destroy pathogens, how is it broken down, and how prevalent is it in prescribed medicine?
Benzylpenicillin (Penicillin G)
Active against Gram +ve bacteria (ie pneumococci, streptococci target peptidoglycan biosynthesis) but does not (typically) penetrate Gram -ve Outer membrane
Destroyed by gastric pH (injection)
50% of all antibiotics prescribed
How does penicillin destroy pathogens?
The B-lactam ring mimics the D-ala-D-ala at the end of the peptide in peptidoglycan, this addition prevents the completion of the peptidoglycan bridge which causes a buildup of peptidoglycan precursors which causes the bacteria to be digested by hydrolases
Penicillin: which can affect Gram -ve bacteria and how?
Semi-synthetic penicillins - they have a modified R1 group (ie Amoxycillin & ampicillin) which allows antibiotics to pass through the outer membrane pores of Gram -ve bacteria
Penicillin resistance: how does penicillin resistance work and what solutions do we have for it?
b-lactamases hydrolyse the b-lactam ring of penicillins rendering them inactive
Solutions:
* Combine with clavulanic acid - a b-lactamase inhibitor (Augmentin)
* Synthesise b-lactamase-resistant penicillins e.g. methicillin
Carbapenem antibiotics: where are they obtained from, what do they do, how are they administered, and what are they used to treat?
Developed in the 1960s as b-lactamase inhibitors obtained as natural products from Gram +ve organisms
Acylate penicillin-binding proteins after entering Gram –ves via porins in the outer membrane
Administered intravenously- does not cross the gastrointestinal membrane
Used to treat b-lactamase-producing (i.e. penicillin) resistant bacteria
Carbapenem resistance: the two types
1 - Three classes of enzymes which hydrolyse the b-lactam ring:
- Class A: Carbapenemases - hydrolyse β-Lactams
- Class B: metallo-β-lactamases (MBL) - makes bacteria resistant to a broad range of B-lactams
(Enterobacteriaceae and environmental bacteria) - Class C: β-lactamases - cleave the B-lactam ring of oxacillin which is resistant to all other B-lactamases
(reservoir in environmental bacteria and deep sea microflora)
2 - mutations that reduce the influx or increase efflux of the drug
MRSA: what is it, what treatments are there for it, how do they function, and (I have no clue but try remember this)?
Methicillin-resistant Staphylococcus aureus (includes beta-lactam antibiotics: penicillins (methicillin, dicloxacillin, nafcillin, oxacillin, etc.) and the cephalosporins)
Vancomycin (also a cell wall inhibitor) - binding to the D-Ala-D-Ala prevents cell wall synthesis in two ways: prevents the synthesis of the long polymers of N-acetylmuramic acid (NAM) and N-acetylglucosamine (NAG) that form the backbone strands of the bacterial cell wall, and it prevents the backbone polymers that do manage to form from cross-linking with each other
MRSA strains contain the mecA gene which encodes penicillin-binding protein 2A with low affinity for b-lactam antibiotics and therefore transpeptidase enzymes are unaffected and can function in the presence of b-lactam antibiotics.
The large hydrophilic molecule is able to form hydrogen bond interactions with the terminal D-alanyl-D-alanine moieties of the NAM/NAG-peptides. Under normal circumstances, this is a five-point interaction
Vancomycin: what is it and where is it obtained, when is it used, and what does it do
a glycopeptide antibiotic - a naturally occurring antibiotic isolated in Borneo in 1953 from Amycolatopsis orientalis
Drug of last resort (ie used to treat MRSA)
Inhibits cell wall synthesis in Gram +ve bacteria when it binds to the terminal D-Ala-D-Ala dipeptide and inhibits transpeptidase activity
Vancomycin resistance: why is resistance different to normal resistance and how does it work?
Because vancomycin does not interact with cell wall biosynthetic enzymes but forms complexes with peptidoglycan precursors, its activity is not determined by the affinity for a target enzyme but by the substrate specificity of the enzymes that determine the structure of peptidoglycan precursors
Resistance to vancomycin is due to the presence of operons that encode enzymes for the synthesis of low-affinity precursors, in which the C-terminal D-Ala residue is replaced by D-lactate (D-Lac) or D-serine (D-Ser), thus modifying the vancomycin-binding target
Aminoglycosides: what are they, what do they do, how are they administered, when are they used, why are they not always used, and which types of bacteria do they affect?
Bactericidals (ie kanamycin & gentamycin, streptomycin) derived from the Streptomyces genus
1) Binds to the 30S ribosomal subunit, preventing active ribosome formation
2) Appear to displace cations in the bacterial cell biofilm that are responsible for linking the lipopolysaccharide (LPS) molecules characteristic of Gram-negative bacterial cell walls, creating holes (lysis) in the cell that may kill the bacteria before the aminoglycoside even reaches the ribosome.
Since they are not absorbed from the gut, they are administered intravenously and intramuscularly.
Used when treatment is required before infecting agent has been determined (ie septicaemia)
Nephrotoxicity and ototoxicity (inner ear damage) during aminoglycoside treatment makes physicians reluctant to use these compounds in everyday practice. Only used for emergencies
Works on both Gram +ve and -ve bacteria (but only really used for -ve as there are many, less toxic alternatives for Gram +ve infections) but only effective on aerobic bacteria as they need energy derived from aerobic metabolism to cross membranes and enter the cell
Tetracycline: what is it and where is it obtained from, what does it do, what is it used to treat, why are eukaryotic cells not affected, how does resistance occur, and what side effects are there?
Tetracycline is a broad-spectrum polyketide antibiotic produced by the Streptomyces genus of Actinobacteria, indicated for use against many bacterial infections
It is a protein synthesis inhibitor
It is commonly used to treat acne today, and, more recently, rosacea, and is historically important in reducing the number of deaths from cholera.
30S ribosomes only affected - eukaryotic cells safe
Resistance to the tetracyclines results from changes in the permeability of the microbial cell enveloaseape.
Can stain developing teeth (even when taken by the mother during pregnancy) Can cause permanent teeth discolouration (yellow-grey-brown); infancy and childhood to eight years old
Macrolides: what are they, what are the ideas behind the mechanism, what is the effect of macrolide, who is it used to treat, and why?
Macrolides are protein synthesis inhibitors (bacteriostatic)
Mechanism of action of macrolides is not fully understood, possibly inhibition of bacterial protein biosynthesis by preventing peptidyltransferase from adding the peptidyl attached to tRNA to the next amino acid and inhibiting ribosomal translocation or possibly premature dissociation of the peptidyl-tRNA from the ribosome.
The addition of an incoming tRNA and its attached amino acid to the nascent polypeptide chain is inhibited
Used in individuals with allergies to penicillin, generally used to treat Gram +ve infections with limited use of Gram –ve (resistance is common)
Nucleic acid synthesis inhibitors: what types are there and how do these inhibitors work?
Fluoroquinolones (synthetic)
Bind to DNA gyrase, preventing it from supercoiling DNA and inhibiting DNA replication
Antimetabolites: what are they, what were they used for and what are they used for now, how is resistance reduced, and how often are adverse effects seen?
Sulphonamides and Trimethoprim (bacteriostatic) Inhibit dihydropteroate synthase and dihydrofolate reductase - both required for folate synthesis
Used in wars on wounds before penicillin, now used to treat acne and UTIs
Both drugs used in combination to reduce the development of resistance
Adverse side effects in 3% population
Teixobactin: what is it and how does it work?
Peptide-like antibiotic which targets Gram +ve bacteria
Binds to lipid II (a peptidoglycan precursor) and forms fibrillar oligomers with Lipid II which obstruct peptidoglycan biosynthesis and causes membrane defects by displacing polar lipid head groups as membrane thickness is reduced
Malacidin
Bind to calcium; the calcium-bound molecule then appears to bind to Lipid II
Retinoids
Vitamin A analogues can kill MRSA
How old is antibiotic resistance?
β-lactamases arose >2 billion years ago, (pre-dating the divergence of Gram +ve and Gram -ve bacteria)
Antibiotic resistance genes are therefore predicted to have been present in environmental bacterial populations for millions of years.
Superbugs
Pathogenic bacteria resistant to most usual antibiotics:
1 - penicillin-resistant pneumococci (Streptococcus pneumoniae)
2 - multidrug resistant mycobacteria (Mycobacterium tuberculosis)
3 - methicillin (meticilin) resistant Staphylococcus aureus (MRSA) sensitive to vancomycin but resistant to all others
4 - vancomycin-resistant MRSA resistant to all usual antibiotics (VRSA – rare but worrying)
5 - Commensals - vancomycin-resistant enterococci (VRE) (rare) (Enterococcus faecalis) commensal that transfers vancomycin resistance to MRSA
Reasons for antibiotic resistance
1 - Natural resistance (intrinsic or innate):
* lack of target structure (ie no wall)
* impermeable to the antibiotic
2 - Sensitive bacteria develop resistance (acquired):
* enzymatic inactivation of antibiotic
* modification of the target
* organism pumps out the antibiotic (efflux mechanism)
How does antibiotic resistance develop?
1 - Selection pressure of antibiotic
2 - Rapid cell division
3. transfer of resistance genes; species to species; genus to genus (HORIZONTAL GENE TRANSFER)
Transfer of R-genes
Methods involving a narrow host range (between members of the same species):
* transduction (from bacteriophages)
* transformation (from naked DNA)
Methods involving a broad host range: between different genera (most important):
* Conjugation-transfer of plasmids
Conjugation mechanism
1 - Donor cells (males) contain plasmid
2 - Recipient cells (females) do not
3 - Mating pairs form (top left)
4 - Pilus retracts & R plasmid transfers to recipient cell (plus resistance genes)
5 - Mating involves cell-to-cell contact
Resistance mechanisms: three mechanisms
1 - Resistance to ß-lactams (penicillins):
* Cleave the ß-lactam ring
2 - Resistance to aminoglycosides (eg streptomycin):
* enzymes inactivate antibiotics by adding groups (eg acetyl, adenyl) - modified antibiotic reduces transport into the cell
3 - Active efflux:
* pumps out the antibiotic immediately using cytoplasmic membrane proteins
Resistance mechanisms: modifications of the target
One example is Resistance to ß-lactams (penicillins):
* Transpeptidase (penicillin binding protein: PBP) has an altered shape preventing penicillin binding but still allowing D-ala-D-ala binding - cross-linking of PG not inhibited & normal PG is produced
