Resistance Flashcards
Resistance
A disease causing age can survive and grow in the presence of concentrations of a chemotherapeutic agent that can safely be achieved in a patient. The drug no longer acts to kill/inhibit the disease causing agent
Consequences of resistance
Increase mortality. Increased morbidity from longer illness and increased spread of restistant organisms. Increased cost from prolonged hospital stays and novel drug costs.
MRSA
Mean population-weighted prevalence in Europe in 2014 was 17.4 (Hassoun et al, 2017). Methicillin-resistant Staphylococcus aureus. Achieved by bypass pathway from that inhibited by drug.
Mortality predictions of resistance
In 2050 10 million deaths will be due to antimicrobial resistance.
Mechanisms of antimicrobial resistance acquisition
Endogenous spontaneous mutation leads to resistance. Horizontal gene transfer from a pre-resistant organism (either from intrinsic resistanfce or from the antibiotic-producer organism)
Mechanisms of horizontally acquired ABx resistance
Genetic vehicles e.g. plasmids, transposons, or Mechanisms of transfer e.g. conjugation, transduction and transformation
Cause of resistance to emerge
Selection pressure of ABx drives survival of the fittest evolution.
Mechanisms of resistance
Altered target site.
Inability to gain adequate, intracellular drug concentrations.
Modification or degradation of drug by enzymes
New, bypass pathway to avert that inhibited by drug.
Risk factors of an ABx or a bacteria for resistance
ABx which act at a singular binding target site.
Bacteria which are naturally transformable species (able to take up DNA fragments in environment and incorporate them into their genome).
Mosaic gene for target of drug
Mechanisms for altered target sit
Modification of drug target.
Mutation. of drug target.
Overproduction of drug target.
Mechanisms for inadequate, intracellular drug concentrations
Poor drug uptake.
Active efflux of drug.
Example of mutated target site
Rifampicin and S.aureus. Mutation in a single amino acid of 4 different residues will cause a huge reduction in the affinity which Rifampicin can bind to RNA polymerase and decrease the drugs activity.
Example of mosaic gene resistance
Penicillin binding protein gene is mosaic and recombinant in Neisseria and Streptococcus due to species being naturally transformable, create altered target for beta-lactams.
Modification of drug target definition and example
NOT GENETIC CHANGE. Post-translocational changes. e.g. Vancomycin resistant enterococci. Create d-alanine-d-lactate able to be used in cell wall biosynthesis but no H bond can form with Abx. Decrease affinity. Minimum change in 5 genes - vanR, vanS, vanH, vanA, vanX.
5 genes in vancomycin resistant enterococci
vanR - signal transduction of vanS message.
vanS - sense presence of vancomycin.
vanH - synthesise d-lactate from raw materials.
vanA - ligase to form d-ala-d-lac bonds.
van x - peptidase, breaks existing d-ala-d-ala bonds.
Example of increase target expression resistance
Vancomycin resistant S.aureus, lead to much thicker cell wall. Causes therapeutic failure but not full resistance
Origin of vancomycin resistant enterococci genes
Acquisition from soil microbe which produces vancomycin and prevents it from being effected by the chemical.
Example of decreased permeability resistance, most common organisms and drawbacks of mechanism
Mostly gram negative. organisms e.g. beta-lactam resistant Pseudomonas aeruginosa. Limits nutrient influx.
Anti-cancer drug active efflux resistance example
Antibiotic agents: doxirubicin, bleomycin. Vinca alkaloids. Topoisomerase 2 inhibitor etoposide. Due to p-glycoprotein ATP efflux pump from ATP-binding cassette transporter family. Present in healthy cells but expression can be amplified in cancer cells.
Antibiotic active drug efflux example
AcrAB/TolC System in E. coli gives resistant to range of ABx including aminoglycosides, tetracyclines, beta-lactams, macrolides, fluoroquinolones.
2 Examples of degradation of drug by enzyme
beta-lactamases degrade beta-lactams. opens ring structure. Aminoglycoside modification adenylation, acetylation or phosphorylation which prevents drug binding to 16S ribosome RNA.
Class A beta-lactamases
Extended spectrum beta-lactamases. Serine mediated
Class B beta-lactamases
Carbapenemases. Widest spectrum. Metallo/zonc mediated
Class C beta-lactamases
Cephalosporinases, AmpC enzymes. Serine mediated
Class D beta-lactamases
Oxacillinases. Serine mediated. Earliest detected.
Enzymes in amino glycoside modification
AAC (acetyltransferases), ANT (adenyltransferases), APH (phosphotransferases)
Example of target bypass resistance
Methicillin resistant S.aureus carry MecA gene which codes for PBP2A. This is able to carry out function of PBP to enough extent to cause cross-linking of peptidoglycan but not acted on by methicillin. E.faecium and PBP5 similar mechanism.
Beta-lactam restante mechanisms
Beta-lactamases modifying drug. Alter target/PBP in Neisseria and Streptococcus species. Decrease permeability in beta-lactam resistant Pseudomonas aeruginosa
P-glycoprotein and agents resistance
P-glycoprotein and ABC transporter presence decrease intracellular drug concs of naturally occurring chemotherapy agents which have hydrophobic aromatic ring and positive charge at a neutral pH. E.g. Vinca alkaloids, Dactinomysin and anthrcycline antibiotics, topoisomerase 2 inhibitors.
2 examples of resistance to the antifingal class Azoles
Candida are resistant via active efflux of drugs via an ATP binding cassette transporter from CDR genes. C.albicans are resistant via altered target - lanosterol 14-alpha demethylase is over-expressed and has a mutation at ERG11 to decrease affinity.
Overcome p-glycoprotein resistance
Administer calcium channel blocker e.g. verapamil to inhibit pump but has ADRs.
Natural expression of p-gp
kidney, liver, gastrointestinal tract, the endothelial cells of the brain and testis, adrenal glands, bone marrow stem cells, and normal peripheral blood lymphocytes
