MIC 205: Exam 3 Ch 10 - Controling microbial growth in body

What is the key factor for antimicrobial action in the body

Selective toxicity

What are drugs

Chemicals that affect physiology (we only want to affect physiology of microbes)

What is selective toxicity

A drug that kills harmful microbes without damaging the host

What are chemotherapeutic agents

Drugs that act against diseases like antimicrobials designed to treat infections

What are examples of chemotherapeutic agents

- Penicilin (antibacterial)
- Tylenol (pain med - headaches)
- Insulin (sugar control)
- Birth control pills
- Zanax (anti-anxiety)
- Viagra, acne meds
- Caffiene, alcohol
- THC, acid, PCP, meth

What are most antimicrobials in use today

Secondary metabolites produced by fungi and bacteria

What is the history of antimicrobial agents

1/3 of children born in early 1900s died from infectious diseases before age five
- Majority of antibiotics were discovered from 1940-1980

What is salvarsan (arsphenamine)

First modern chemotherapeutic agent discovered by Paul Ehrlich in 1910. Arsenic compound used to treat syphilis

What is penicillin

Discovered by Alexander Fleming in 1929. Not available routinely until late 1940s. Produced by Penicillium mold
*he discovered by mistake

What is sulfanilamide

Discovered by Gerhard Domagk in 1932. First widely available and practical antimicrobial agent. Inhibits metabolic synthesis of DNA and RNA nucleotides
*this was the drug of choice before WW2

What has the most number of useful agents and least number of useful agents

Antibacterial has the most useful agents and antiviral has the least useful agents

Describe aspects of selective toxicity

- Kill the pathogen but not the host
- Antibacterial drugs constitute the largest number and diversity of antimicrobials
- Fewer drugs available for treatment of eukaryotic infections
- Effective antiviral drugs are rare!

What type of cells have more similarity to human cells

Yeast cells have more similarity to human cells meaning less targets

What are mechanisms of antimicrobial action

- Inhibition of cell wall synthesis
- Inhibition of protein synthesis
- Disruption of cytoplasmic membrane
- Inhibition of general metabolic pathway
- Inhibition of DNA or RNA synthesis
- Inhibition of pathogen’s attachment to or recognition of host

What is inhibition of cell wall synthesis

Prevents cross-linkage of NAM subunits in newly-synthesized bacterial cell walls
Beta-lactams most prominent in this group → functional portions of molecules are beta-lactam rings

What are beta-lactam rings of inhibition of cell wall synthesis

Beta-lactam rings binds to enzymes that cross-link NAM subunits. Causes bacteria to have weakened cell walls and eventually lyse

What do beta-lactams have an effect/no effect on in inhibition of cell wall synthesis

Effective only for growing cells
Not effective on existing peptidoglycan layer (only inhibits building of peptidoglycan) & not effective on plant or animal cells (possess no peptidoglycan)

What are semisynthetic derivatives of beta-lactams

- More stable in acidic environments
- More readily absorbed
- Less susceptible to deactivation
- More active against more types of bacteria (broad group = kills infection and normal flora)

What is the size of prokaryotic and eukaryotic ribosomes

Prokaryotic ribosomes are the 70S in size (30S and 50S)
Eukaryotic ribosomes are the 80S in size (40S and 60S)
(inner mitochondria posses 70S ribosomes)

How do drugs take advantage of the different in size of prokaryotic and eukaryotic ribosomes

By selectively targeting and inhibiting translation

What ribosomes does mitochondria of animals and humans contain

70S ribosomes → these drugs can be harmful to eukaryotes

What are examples of drugs used for inhibition of protein synthesis

Streptomycin, tetracyclines, erythromycin

What does streptomycin/aminoglycosides do in regards to inhibiting protein synthesis

Change shape of 30S subunits making it impossible for ribosomes to read codons of mRNA correctly

What does tetracyclines do in regards to inhibiting protein synthesis

Block tRNA docking site/A site, preventing additional amino acids into polypeptide preventing translation

What does chloramphenicol do in regards to inhibiting protein synthesis

Binds to 50S portion and inhibits formation of peptide bond preventing amino acid creation

What does erythromycin/macrolides do in regards to inhibiting protein synthesis

Binds to 50S portion, prevents movement of ribosome from 1 codon to the next, stopping translation and protein synthesis

How does disruption of cytoplasmic membrane happen

Some drugs become incorporated into cytoplasmic membrane and damage its integrity

What does amphotericin B do

Attaches to ergosterol found in fungal membranes → its an antifungal agent

Are humans susceptible to amphotericin B

Humans are somewhat susceptible because cholesterol is similar to ergosterol (bacteria lack sterols → not susceptible)

What is inhibition of metabolic pathways

Drugs target differences between metabolic processes (enzymes) of pathogen and host (antimetabolic agents)
*like sulfanilamide inhibiting PABA synthesis

What are metabolic mechanisms of the intervention of inhibition of metabolic pathways

- Heavy metals inactivate enzymes
- Agents that rid the body of parasitic worms by paralyzing them
- Drugs block the activation of viruses
- Metabolic antagonists (including enzyme inhibitors)

What are sulfa drugs

Inhibit metabolic pathways used for biosynthesis of DNA and RNA nucleotides

What are sulfonamides a structural analog of

PABA
*When sulfanilamide binds, PABA does not get converted because it is a competitive inhibitor that prevents PABA from binding resulting in cell death

What is PABA used for

Synthesis of nucleotides required for DNA and RNA synthesis

What do some enzymes convert PABA into

Dihydrofolic acid that then gets converted to tetrahydrofolic acid (THF)

What are nucleic acid analogs

A class of drugs that are structurally simillar to nucleotides of RNA and DNA but are missing certain atoms which causes termination of the synthesis of nucleic acid

Describe viral polymerase in regards to errors

Viral polymerase tend to be error-prone and are unable to distinguish between the normal nucleotide and the analog

What are examples of nucleic acid analogs

- Acyclovir: used as herps medication which terminates DNA replication
- Remdesivir: used as COVID 19 medication which terminates RNA replication
- Retrovir: used as HIV medication which terminates RNA replication

What is the last step of viral replication (inhibition of attachment (influenza))

Last step of viral replication is the function of Neuraminidase (N) that cuts off sialic acid from hemagglutinin to allow the release of the virus from the host cell

What does Relenza and Tamiflu have similar structure to

Relenza and Tamiflu have structural homology to sialic acid. Therefore, the drug (competitive inhibitor) will bind to the neuraminidase and prevent the release of the new viruses from the host cell

Where will the new virions remain after inhibition of attachment (influenza)

New virions will remain struck to the host cell that just replicated in them and will inhibit new virions’s attachment to new cells

What are ideal antimicrobial agent

- Inhibit cellular processes specifically
- Cheap
- Available
- Easily administered
- Low side effects
- Stable

What is spectrum of action

Broad-spectrum drugs may allow for secondary or superinfections (new infection on top of an old infection) to develop and kill normal flora, reducing microbial antagonism

What is spectrum of action and broad spectrum drugs

Spectrum of action: number of different pathogens a drug acts against
Broad spectrum drugs: attack many different pathogens and allow for secondary infections

What tests can you run to test the efficacy of antibacterial agents

Disk-diffusion (kirby-bauer) tests, minimum inhibitory concentration (MIC) test, minimum bactericidal concentration (MBC) tests

What is the disk-diffusion (Kirby-Bauer) test

Tests the effectiveness of antibiotics on a specific microorganism

What is minimum inhibitory concentration (MIC) tests

Determines the lowest concentration of an antimicrobial agent that prevents the growth of a microorganism

What is minimum bactericidal concentration (MBC) tests

Determines the lowest concentration of an antibacterial agent required to kill a particular bacterium

What must antimicrobial agent do to be effective

Antimicrobial agent must reach the site of infection and the concentration must be above the MIC if it is to be effective
- Drugs are constantly being removed from body
- Many drugs can’t cross blood-brain barrier

What is the 2 routes of administrations for antimicrobial drugs

External infections and internal infections

What is used to treat external infections as a route of administration for antimicrobial drugs

Topical (local): direct application of creams and pastes to the skin

What is used to treat internal infections as a route of administration for antimicrobial drugs

- Oral: simple, but patients don’t always follow prescription instructions; has the lowest effectiveness
- Intramuscular (IM): direct injection into muscle tissue
- Intravenous (IV): direct administration into bloodstream by needle or catheter; achieves highest level of the drug in the body in the shortest amount of time

What are side effects of some antimicrobial drugs

Toxicity, allergies, and disruption of the normal flora

What is toxicity of antimicrobial drugs and examples

Drugs can be toxic to kidneys, liver, and nerves
- Tetracycline forms calcium complexes that damage teeth and bones
- Metronidazole (anti protozoan drug): causes hemoglobin remnants to collect on tongue

What are allergies of antimicrobial drugs

Rare but life threatening

What are disruption of the normal flora of antimicrobial drugs

Yeast infections and Pseudomembranous colitis

What are 2 ways bacteria acquire drug resistance

Spontaneous mutations of chromosomal genes
Acquisition of antibiotic resistant plasmids by transformation, transduction, and conjugation

How does a bacterial population become resistance

When the resistant microbes are the majority of the population
- Due to an individual not taking the drug to completion or missing the dose time perimeters
- Overuse to non-necessary cases

What are bacterial reisistance mechanisms

1. Production of an enzyme that inactivates or destroys an antibiotic like penicillin or other beta-lactams (ability to produce beta-lactamase enzyme is one of the most common resistances in disease-causing bacteria)

2. Prevention drug entry into bacterial cell by changes in membrane proteins

3. Alteration of the drug’s receptor within the bacterial cell wall, cytoplasm, or membrane

4. Alteration of the cell’s metabolic chemistry

5. Expression of multidrug resistance proteins that pump drugs out of the cell before they can act

What are methods for retarding resistance

• High concentrations of drug maintained in a patient for a long enough time to kill all sensitive cells and inhibit others long enough for the immune system to destroy them

• Use antimicrobial agents in combination (synergism)

• Limit use of antimicrobial to necessary cases

• Development of new variations of existing drugs by adding novel side chains to original molecule (2nd and 3rd generation drugs)

• In some extreme cases, anti-cancer drugs are now being used

  *viruses have no peptidoglycan so theres no need to