Topic 5: Antimicrobial agents and resistance Flashcards
what does an antiseptic do
kill bacteria, viruses and protozoa, too harsh for internal use
skin
what does a disinfectant do
kill bacteria, viruses and protozoa, too harsh for internal use
surfaces
what are antibiotics
Low molecular mass compounds that kill or inhibit the growth of bacteria and can be
ingested or injected into the human body with minimal side effects
what are the requirements of an antibiotic
killing/inhibition
- bacteriostatic ok for intact immune system, defective needs bactericidal
selective toxicity
- differences between host and pathogen
pharmacokinetics
- does it get where it needs to
what makes a good antibiotic
Few side effects
Broad spectrum (symptoms often common between causes)
BUT may destroy natural flora allowing other organisms in (yeast vaginitis)
what are the antibiotic targets
cell wall biosynthesis
nucleic acid synthesis
protein synthesis
cytoplasmic membrane function
antibiotic targets - cell wall biosynthesis
peptidoglycan is unique to bacteria and essential for viability
beta-lactams - bind and inhibit penicillin binding proteins which are involved in transpeptidation and transglycosylase reactions
glycopeptides - bind to D-ala-D-ala prevent transpeptidation and transglycosylase reactions -last resort due to toxicity
what are Transpeptidase and Transglycosylase Reactions (google bard)
Transpeptidase reaction: This enzyme links short sugar chains together in the peptidoglycan by forming bonds between amino acids (proteins). By mimicking this building block, β-lactam antibiotics essentially block the transpeptidase’s “active site,” preventing it from attaching new sugar chains.
Transglycosylase reaction: This enzyme builds the sugar backbone of peptidoglycan by linking sugar molecules together. Glycopeptide antibiotics interfere with this process by hindering the transglycosylase enzyme from doing its job
antibiotic targets - nucleic acid synthesis
targets include inhibiting the synthesis of precursors which are not made by humans (in diet)
inhibit DNA gyrase (supercoiling)
RNA polymerase (rifampicin)
antibiotic targets - protein synthesis
bacteria ribosomes are different to human ones
can bind to the 50S subunit and block the transfer of peptides
or bind the 30S to prevent it binding to 50S - comes with more side effects eg. kidney function/hearing loss
or bind 30S to prevent alignment of aminoacylate tRNA with mRNA.
antibiotic targets - cytoplasmic membrane function
leak H+ pmf dissipate
eg.s of beta-lactams
penicillin, methicillin, cephalosporins
what is the definition of resistance
A resistant organism is one that will not be inhibited or killed by
an antibacterial agent at concentrations of the drug achievable in
the body after normal dosage
what are the causes of resistance - healthcare
over prescription (no diagnosis, misdiagnosis)
over the counter
improper use by patients
what are the 2 types of resistance
innate: natural - lack of target/impermeable
acquired: can be through reduced uptake, efflux, inactivation of drug or alteration of target
what are the causes of resistance - agriculture
this can be caused by the use of antibiotics for increased growth, prophylaxis or treatment of disease
spreads to humans through contact consumption or the environment
what is the genetic basis of resistance
point mutations
new genetic material
conjugation (direct DNA transfer)
transposons
plasmids
tackling antibiotic resistance
drug development - empirical screening and rational design
vaccines - Community acquired bacterial infections
Hospital acquired bacterial infections
Viral infections
Veterinary vaccines
Acquired Antimicrobial Resistance: Reduced Uptake Method
Reduced Uptake - Outer membrane porins are non-specific channels, a single mutation can increase resistance 5-10 fold for many drugs - which can quickly spread through a population
Acquired Antimicrobial Resistance: Efflux Method
Efflux - Multidrug resistance (MDR) exporter (AcrB in E.coli) Tetracycline actively pumps out the drug from within the cell (if it operates intracellularly)
Acquired Antimicrobial Resistance: Inactivation of Drug Method
e.g. Beta-lactamase hydrolyses the lactam ring of penicillin (common in gram negative bacteria)
Acquired Antimicrobial Resistance: Alteration of target Method
e.g. Beta lactams -> alteration in Penicillin Binding Proteins (PBP) e.g. mosaic PBP encoding genes in Streptococcus pneumoniae
What structure (viral-phage-like particles in bacteria) protects bacteria from toxic substances?
Encapsullins
What are the current notable cases of growing antibiotic resistant pathogens?
MRSA (VRSA)
Mycobacterium Tuberculosis -> costing 1 billion dollars to NY alone.
NDM-1 in E.coli resistant against carbapenem.
What are the requirements for scalable diagnostic techniques?
Rapid, achievable at point of care, and cheap.
What are the benefits of large scale vaccination projects?
-Reduce the number of bacterial infections requiring antibiotics (reducing developing resistance)
-Reduce the number of infections (hospitalisations and fatalities)
-Reduce the number of viral infections in which antibiotic unnecessarily given.
Properties of conjugative plasmids:
Self transmissible (>25kb), mobilisable, can carry multiple resistance genes
What are the qualities of an ideal antibiotic target:
Present in bacterium but not in human and essential for the pathogen’s survival.
Examples of glycopeptide antibiotics:
Vanomycin, teichoplanin
Examples of beta-lactams antibiotics:
Penicillin, methicillin, cephalosporins
What are examples of new antibiotics?
Synercid, Linezolid and Daptomycin
What is Synercid?
A new antibiotic which is a mixture of dalfopristin and quinupristin (mixing drugs makes bacteria more susceptible) -> both are streptogramins (binding to the 50S subunit of the ribosome) and inhibits translation (by preventing peptide elongation) -> resistance has developed due to use in agriculture.
What is Linezolid?
A new antibiotic which is a oxazolidinone, binding to the 50S subunit of the ribosome and preventing the initiation of protein synthesis
What is Daptomycin?
A new antibiotic which interacts with many sites across the target weakly on the cell surface, the culmination of these weak interactions (and multiple insertions in the membrame) leads to the formation of a pore in the membrane -> its mechanism of lysis is unknown but is linked to the pumping of K+ out of the cell and is Ca2+ dependent. Because of its unique mechanism it’s able to treat “undruggable” targets -> however resistance developed in 2005.
Why are bactofilins a good target when using a mixture of drugs in an antibiotic mixture?
Targeting bactofilin makes the targeted cell 50x more sensitive to cell wall targeting antibiotics
What is an example of a disinfectant?
Lister’s phenol -> can cause burns on skin
