Mechanisms of Drug Resistance Flashcards
Genetic composition of the cell undergoes spontaneous alteration by
Mutation of gene transfer
Provides a strong selective pressure in favor of the resistant cell by preventing growth of the wild-type, sensitive cells
Drug
May have mutagenic properties and non-specifically increase the probabilities of many kinds of mutation
Bacteriostatic drugs
Estimated to cause more deaths in the US than AIDs
Methicillin-resistant Staphylococcus Aureus (MRSA)
Anti-microbial resistance is more prevalent in strains that cause infections in
Hospitals
During outbreaks of infections, patients with resistant strains are more likely to have received prior
Animicrobial therapy
Areas in hospitals with highest antibiotic use have highest incidence of
Drug resistant bacteria
What are the four mechanisms by which bacteria can acquire drug resistance?
Transformation, Transduction, Conjugation, Transposition
Small pieces of DNA containing genes for drug resistance are taken up from the environment and incorporated into the genome of a drug-sensitive bacterium
Transformation
Resistance genes are transferred from one bacterium to another by a bacteriophage
Transduction
Drug resistance genes contained in a plasmid are transferred from one cell to another through a direct connection formed by a pilus
Conjugation
Allows resistance genes to move between plasmid and chromosomal (genomic) DNA
Transposition
The first biochemical mechanism of drug resistance is decreased intracellular drug level due to either
Decreased drug entry or increased drug efflux
Gm- bacteria with mutations that alter porin proteins, thereby decreasing passive drug diffusion is an example of
Decreased intracellular drug level
Resistance to tetracyclines can occur through acquisition of genes that encode an active
Efflux of the drug
The second mechanism for drug resistance is increased
Drug inactivation
Can produce enzymes that render antibiotics biologically inert
Bacteria
An example of this is the enzymatic cleavage of penicillins and cephalosporins by
B-lactamases
Drug resistance can also occur from decreased conversion of a drug to a more
Active compound
Decreased conversion of a drug to a more active compound occurs most often with drugs that act as
Antimetabolites
Resistance to the antifungal agent 5-flucytosine due to decreased activity of UMP pyrophosphorylase is an example of
Decreased conversion of a drug to a more active compound
Drug resistance can also occur by increased conversion of a metabolite that functions as a
Drug antagonist
If the drug acts as an antimetabolite, then increased production of the normal metabolite will compete for the drug effect and lead to
Resistance
An example of increased concentration of a metabolite that antagonizes drug action is the resistance to sulfonamides by an increase in
p-aminobenzoic acid (PABA)
An altered amount of target enzyme or receptor can also confer
Drug resistance
Mutation in a regulatory gene (e.g., a repressor) can control the expression of the gene encoding the
Target
When the gene for the receptor undergoes a mutation that changes the conformation of the drug binding site, we see a
Decreased affinity of receptor for drug
Trimethoprim resistance by producing DHFR with reduced affinity for the drug is an example of
Decreased affinity of the receptor for the drug
Mutants deficient in autolytic enzymes, which breakdown sections of the proteoglycan (PG) matrix during growth can cause
Drug resistance
In the absence of autolytic enzymes, drugs that inhibit cell wall synthesis
Bacteriostatic rather than bactericidal (tolerance)
A unique form of drug resistance is an alteration of an enzymatic process that is unaffected by the drug, but is necessary for the drug’s
Cytotoxic affect
Binds D-Ala-D-Ala moiety and interferes with formation of PG matrix
Vancomycin
Produces enzymes that generate D-Ala-D-lactate termini that can form PG matrix, but do not bind vancomycin
VanHAX Operon
Resistance is diminishing the effectiveness of
Vancomycin
Administration of sub-inhibitory doses of antibiotics promotes the selection of
Resistant subpopulations
Administer combinations of two drugs with different mechanisms of action and different biochemical pathways of resistance when performing
Antimicrobial Chemotherapy
If resistance mutation frequency is 10-6 for each drug alone, then it will be 10-12 when both drugs are administered in
Combination
To combat bacterial resistance mechanisms, we want to develop inhibitors of drug-inactivating proteins and efflux transporters. An example of this is the use of
B-lactamase inhibitors
