Drug Resistance

Drug tolerance

A reduction in response following repeated or sustained drug exposure, such that a larger dose may be required to produce the original effect

Drug resistance

Described reduced response (or absence of response) to drug treatment. It usually means the drug’s biological targets, such as bacteria, viruses, or cancer cells, can survive or grow despite treatment

Tachyphylaxis

Example of drug tolerance, repeated ephedrine doses deplete norepinephrine, reducing blood pressure response

Chronic drug tolerance

Example of drug tolerance, repeated morphine use produces less analgesia

Not all treatment failures is resistance, all of the following listed can also cause treatment failure except

Mutation of drug

Antibiotics often act on bacterial structures that humans dont have, this can provide a relatively ______ therapeutic window

Wide

Tumor cells are human cells, anti cancer drugs must exploit tumor-specific vulnerabilities while limiting harm to normal tissues, this results in a ____ therapeutic window

Narrow

Resistance can shift the effective concentration _____

Upward

Intrinsic resistance

Resistance that exists naturally in a cell or organism before drug exposure

Intrinsic resistance key features

• Pre-existing

• Due to inherent biological characteristics

• Does not require prior drug exposure

Gram-negative outer membrane limits
vancomycin entry

Intrinsic resistance example

A tumor lacks the drug target or harbors alternative pathways

Intrinsic resistance example

Acquired resistance

Resistance that develops in a previously drug-sensitive cell or organism.

Acquired resistance key features

• Develops through genetic or adaptive
  changes
  Can involve mutations, gene transfer, or
  altered gene expression
  May arise before or during treatment

Bacterial beta-lactamase acquisition

Acquired resistance example

Target mutation in a tumor

Acquired resistance example

Major mechanism of drug resistance (Pharmacokinetic)

Drug does not reach the target - Reduced uptake, impaired delivery, or increased efflux

Drug is inactivated - Enzyme-mediated destruction or
chemical modification

Major mechanism of drug resistance (Pharmacodynamic)

Target changes - Mutation, reduced expression, or altered binding

Cell bypasses the blockade - Alternative metabolic or signaling pathway

Mechanisms of innate (intrinsic) resistance - Pharmacokinetic systemic factors (host)

1. Decreased drug absorption
2. Decreased metabolic activation of the drug
3. Increased metabolism and elimination
4. Decreased drug distribution due to structural or functional barriers (for example BBB)

Mechanisms of innate (intrinsic) resistance - Pharmacodynamic factors

5. Reduced transport inside the pathogen
6. Elevated removal from the pathogen
7. Target is hardly reachable due to specific
cellular barriers or low affinity to the drug
8. Existence of an alternative pathway which can
complement the activity of the targeted pathway

Antibiotic-resistant germs caused more than 2.8 million infections and more than 35,000 deaths in the US every year

Why antibiotic resistance matters

Which of the following is not an approach to avoid innate resistance

Increase concentration of drug

Acquired resistance

Pathogens or tumor cells initially respond to a drug but
become less responsive or resistant over time

Resistance mechanisms (acquired)

Genetic changes (mutations or acquired genes) and, particularly in cancer, epigenetic or adaptive cell-state changes can produce resistant cells.

Selection (acquired)

During drug treatment, susceptible cells are eliminated while resistant cells survive and expand. Acquired resistance can arise through either selection of pre-existing resistant variants or treatment-induced adaptive mechanisms.

Examples of high-burden resistant bacterial threats

Methicillin-resistant Staphylococcus aureus (MRSA) and Carbapenem-resistant Acinetobacter (CRAB)

Gram positive

Purple, cocci (round, spherical), has the additional cell wall

Gram negative

Pink, bacilli (rod-shaped)

Amoxicillin, vancomycin (prevent cell wall synthesis)

Drugs used in gram positive bacteria

Amoxicillin (water soluble, able to cross the lipid membrane by the “watery” porin protein)

Drugs used in gram negative bacteria

Target mutations

Germs change the antibiotic’s target so the drug can no longer fit it and do its job

Antibiotic efflux pumps

Germs can rid of antibiotics using pumps

E.g. porin mutants with decreased affinity

Germs restrict access by changing the entry ways or limiting their numbers

E.g. beta-lactamase destroys beta-lactam antibiotics

Germs change or destroy the antibiotics

Use of alternative enzyme

Germs avoid use of antibiotic’s target

Which of the following is not an example of bacterial resistance mechanisms

Metabolize the drug

Vertical gene transfer

Mutated gene is passed through the bacterial replication to the descendants of this bacterial cell.

Horizontal gene transfer

The sharing of genetic material between organisms
that are not in a parent–offspring relationship.

Which of the following is not a horizontal transfer mechanism

Conformation

Conjugation

Direct cell-to-cell DNA transfer, often by plasmid, Common route for plasmid-borne resistance genes

Transformation

Uptake of free DNA from the environment, DNA released from other bacteria can be incorporated

Transduction

Bacteriophage transfers bacterial DNA, Virus carries DNA between bacteria

MDR1 / P-glycoprotein (P-gp) (ABCB1)

The major drug transporter (transports ~1/2 of all the drugs) in normal tissues and a key contributor to multidrug resistance in cancer

Common multidrug-resistant (MDR)

Cells selected for resistance to drugs with different structures and targets were found be cross-resistant to the other drugs: a ______ phenotype

Which of the following is not a reason why is P-gp inhibition not becoming a routine cancer therapy

P-gp is not expressed in normal protective barriers, including intestine, liver, kidney, and blood-brain barrier.

Target alternation

How Cancer Cells Resist Targeted Therapy - The target protein changes, so the drug binds less well.

Target amplification

How Cancer Cells Resist Targeted Therapy - The cancer produces much more of the target, overwhelming the drug.

Bypass signaling

How Cancer Cells Resist Targeted Therapy - A different receptor or pathway activates the same growth signal.

Downstream pathway reactivation

How Cancer Cells Resist Targeted Therapy - Signaling resumes below the blocked target.

Cell-state or lineage plasticity

How Cancer Cells Resist Targeted Therapy - Cells change phenotype and no longer depend on the targeted pathway.

Drug-tolerant cells and tumor heterogeneity

How Cancer Cells Resist Targeted Therapy - A pre-existing or reversible resistant subpopulation survives, then expands during treatment

Tumor microenvironment support

How Cancer Cells Resist Targeted Therapy - Surrounding stromal cells, hypoxia, or growth factors help cancer cells survive therapy.