Antimicrobial Drugs Flashcards
What is selective toxicity/”magic bullet” ? Who popularized this concept?
Selective toxicity/”magic bullet”: the idea of a drug killing pathogens without damaging the hosts
concept popularized by Paul Ehrlich
What is Chemotherapy? Who coined this term?
Chemotherapy: the use of drugs/chemicals to treat Any disease (broad historical term coined by Paul Ehrlich) - Antimicrobial chemotherapy
What are antimicrobial drugs?
Antimicrobial drugs: compounds that interfere with the growth of microbes within a host
What is an antibiotic ?
Antibiotic: A substance produced by a microbe that in small amounts, Inhibits another microbe (struck definition in text for ch. 20 )
Are sulfa drugs antibiotics? Is ampicillin an antibiotic ?
NO, Sulfa drugs are NOT antibiotics, because it is NOT produced by a microbe
-Ampicllin is a derivative of penicillin
-Ampicllin is Not considered antibiotic according to definition of antibiotic in text (chapter 20)
What is definition of antibiotic using glossary of textbook?
Given in glossary of textbook, an “antimicrobial agent, usually produced naturally by a bacterium or fungus”
What was the first antibiotic discovered? Which scientist were invivled>
The first antibiotic discovered was PENICILIN
-1928: Fleming discovered penicillin produced by a mold from gene Penicillium
-1940: Scientists led by Ernst Chain and Howard Florey began first clinical trials of penicillin
(they experimented putting penicillium on cantaloupe)
-**production was increased by identify another strain of penicillium (200x) in 1943 then irradiating it to yield 1000x.
what is an antibiotic class?
Antibiotic class: a grouping of related antibodies
What has occurred in amount of antibodies over time?
Early on in time line, a lot of antibiotics were being discovered. overtime. the discoveries have Decreased due to the “‘low hanging fruit” is gone (discovery of antibiotics are
Explain why pharmaceutical companies put very little investment in the developmental of new antibiotics?
These companies put little investment in development of new antibiotics because:
-Difficult to Identify new mechanisms, and kill pathogens
-generate small revenue ( require short prescription course , use of new antibiotics is kept low)
REVEIW
What is Antibiosis? what mediates it?
Antibiosis: An associate of two orgnamiss in which one is harmed or killed by the other.
-Antibiosisis is generally mediated by the production of LOW molecular weight antibiotics by the antagonist
How many species in environment are uncultured?
Approximately 99% of ALL species in external environment are uncultured
What is ICHIP ? Why is it useful? What bacterium can be identified using the method?
IChip; Isolation Chip (method of culturing bacterial species within its soil environment; it will sort individual bacterial cells that are harvested from soil into single chambers)
With this culturing method, about 50 to 50 percent of bacterial species are able to survive (compared to 1% soil organisms that grown on nutrient dish).
It allowed discovery of new organism ** Eleftheria terrae ** that produced teixobactin
Explain the process of ICHIP. What occurs?
process:
1. The isolation Chip consists of hundreds of small holes. 2. Following dilution of soil in molten algar and nutrients, it is hoped that only one microbe is caught in each of the IChip’s small compartments.
3. The IChip is then covered with membranes on both sides with pores only large enough for naturally occurring growth factors to flow in, but small enough to block movement of any bacteria .
4. They are then put back into the soil.
With this culturing method, about 50-60% bacteria are able to survive (compared to 1% soil) organisms that grow on nutrient dish)
What types of microbes produce most antibiotics?
What are other microbes that produce antibiotics
Actinomycetes, especially Streptomyctes species produce the most antibiotics
-(gram positive rods, fungi also produce antibiotics)
Actinomycetes (action= ray) filamentous or branching growth.
The informal name for bacteria in order actinomycetales is phylum Actinobacteira
Which genus produces more than half of our antibiotics?
STREPTOMYCETES
What are two characteristics doo almost all antibiotic producing microbes have in common
They all produce SPORES
-They live in SOIL
Differentiate between broad spectrum antimicrobials and Narrow-spectrum antimicrobials
Broad spectrum antimicrobials; acts against a wide range of microbes (ex: describe gram positive and gram negative)
Narrow spectrum antimicrobials : are effective against specific groups of microbes (ex: discussing only gram negative bacteria)
broad and narrow can be relative terms
Some sources list streptomycin as broad spectrum and others narrow spectrum (broad and narrow are usually qualified)
Recognize that different drugs can be classified as antibiotics depending
on how “antibiotic” is defined
streptomycin can be considered part of broad spectrum; other see it as narrow spectrum
-Isoniazid used for mycobacteria (narrow spectrum)
-Penicillin G (Gram-positive bacteria) (narrow)
-Tetracycline used for gram negative and gram positive bacteria (broad)
-Ketoconazole —> fungi (broad spectrum? )
-mefloquine (malaria; part of protozoa) (narrow?)
-Niclosamide (tapeworms; part of helminths) (narrow?)
-Praziquantel (flukes; part of Helminths) (narrow?)
-Acyclovir for viruses (broad?)
REVIEW
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what is the advantage and disadvantage of treating a bacterial infection with a broad spectrum antibiotic?
Treating bacterial infection with broad spectrum:
Advantage: effective treatment is more likely when the identity of pathogen is NOT yet known
Disadvantage: Destroys normal microbiota that ordinarily compete with and check the growth of pathogens and other microbes
What are the two definitions for superinfection ?
Superinfection (Two definitions)
1st definition: Superinfection: a second infection occurring during the course of an existing infection, usually caused by the antibiotic destruction of normal microbiota an the overgrowth of opportunistic pathogens unaffected by the antibiotic (ex: gut overgrowth of Clostridium difficile and or Candida albicans )
2nd definition: Superinfection: an infection by the same organism following a previous infection, especially when the target microbe has become resistant to the antibiotics used earlier
Term is also applied to several other conditions
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Why are the two organisms( Clostridium difficile and Candida albicans) not affected by initial antimicrobial treatment?
Because they are naturally RESISTANT to antibiotics
How can antimicrobial drugs be classified as?
Antimicrobial drugs are classified as either Bacteriocidal or bacteriostatic
Differentiate between bactericidal and bacteriostatic
Bactericidal: Kills microbes directly
Bacteriostatic: prevent microbes from growing
-Host’s defenses (antibody production and phagocytosis) usually destroy organisms
What are the 5 ways that antimicrobrial drugs target bacterial cells (selective toxicity) ? provide examples of bacteria
5 ways that antimicrobial drugs target bacterial cells:
1. INHIBITION of cell wall synthesis: penicillins, cephalosporins, bacitracin, vancomycin
2. INHIBITION of protein synthesis : chloramphenicol, erythryomycin, tetracyclines, streptomycin (inhibit translation)
3. INHIBITION of nucleic acid replication and transcription: quinolones, rifampin
4. INJURY to plasma membranes : Polymyxin B
5. INHIBITION of essential metabolite synthesis : sulfonamide, trimethoprim
Why is it more difficult to find or develop antimicrobials effective against fungi (relative to bacteria)
because there are more targets for selective toxicity in bacteria (whereas in fungi not a lot)
(fungi are more similar to human cells (genetically) more than bacteria, so its more difficult to find targets for toxicity)
-harder to find drugs that can attack fungi without damaging human cells
Why is there concern that antibiotics that target bacterial ribosomes could adversely affect the cells of the host?
Because the mitochondria of eukaryotic cells contain 70s ribosome
What is a common antimicrobial target in fungal plasma membranes?
STEROLS
Why does penicillin only affect actively growing cells?
because only peptidoglycan synthesis is targeted
Why do antimicrobials that target replication and transcription generally have limited medical usefulness?
because most also interfere with mammalian DNA/RNA
What are the antimicrobial drugs that are part of classes of Bacterial cell wall synthesis inhibitors ? what are the members involved in the classes?
Classes of Bacterial Cell Wall Synthesis Inhibitor :
1. Penicillin (over 50 chemically related antibiotics with a common core structure)
-Natural penicillins:
-Semisynthetic penicillins :
> Extended- spectrum
> Penicillinase resistant
2. Carbapenenms
3. Monobactams
4. Cephalosporins
5. Polypeptide Antibiotics
-Vancomycin
-Bacitracin
What does penicillin inhibit? What do carbapenem, monobactam and cephalosporin inhibit?
Penicillin inhibits the cross linking of peptidoglycan layers (peptidoglycan made of NAG and NAM)
Carbapenem, monobactam, and Cephalosporin inhibits the same enzymes
What is the role of the penicillin binding proteins (PBPs) ? What happens when PBPs bind penicillin?
REVIEW slide 25
Penicillin binding proteins (PBPs) bind the Beta-lactam ring of beta-lactam antibiotics, which mimics acyl-D-Ala-D-Ala peptides of peptidoglycan. When PBPS bind penicillin, the Beta-lactam amide bond is RUPTURED to form a covalent bond with catalytic serine, inactivating the enzyme.
Differentiate between two two natural penicillins? What are their characteristics? What do they have in common? which natural penicillin ins the most-widely used one?
Natural Penicillins:
Extracted from the mold penicillium
Penicillin G (requires INJECTION)
Penicillin V (can be taken ORALLY)
both penicillin G and V share a common nucleus that has a Beta-lactam ring
These are most often used natural penicillins (G and V) : prinicipally in the treatment of infections due to *gram-positive bacteria *
-Penicillin G: most Widely used natural penicillin but
requires intravenous or intramuscular administration
-Penicillin V is stable in stomach acids.
What do the letters “G” and “V” designate in natural penicillins?
Natural Penicillins
G—> Gold standard (More potent natural pencillin? )
V—> Latin word for Vesco/Vescor which means to feed, or to eat.
REVIEW
Explain how Penicillin G can be better retained from the body?
Although Penicillin G is rapidly excreted from the body, DRUG COMBINATIONS can extend its retention (allow it to be better retained)
Example of drug combinations
- Procaine penicillin (combine procaine and penicillin) have ration up to 24 months and peak (hightest blood concentration) in 4 hours
- Benzathine penicillin (combine benzathine and penicillin), you will have better retention of penicilin G blood levels for several days (4 months), the drug concentration will be LOW
-organisms must be very SENSITIVE to penicillin G for penicilin benzathine to be effective
Explain why procaine salts and benzathine salts have an extended duration of action?
These penicillin G salts (procaine, benzathine salt) have an extended duration of action because they can distributed into storage tissues to be released slowly into blood stream
(hence why these salts combining with penicillin G, allows for longer retention)
What are the disadvantages of the natural penicillins?
Disadavantages of natural penicillins:
*Narrow spectrum of activity (only gram-positive bacteria) (not always a disadvantage)
-Susceptibiilty to PENICILLINASES (beta-lactamases)
*most common form of resistance to penicillins
What is the role of enzyme penicillinase? Why is natural penicillin effective against gram-positive bacteria, but not gram-negative bacteria?
Penicillinase: enzyme that will cleave beta lactam ring and also convert penicillin to penicilloic acid.
-natural penicillin is effective against gram-positive bacteria (NOT gram-negative) because the natural penicillin CANNOT penetrate the outer membrane
What are Semisynthetic penicillins? How do you obtain a common penicillin nucleus ?
Semisynthetic Penicillins: Natural penicillin that have been chemically modified
- Alternative side chains are chemically added to a common penicillin nucleus to:
-extend antibiotic spectrum
-increase resistance to penicillinase
A common penicillin nucleus is obtained by either:
1) interrupting the organism’s synthesis of penicillin or
2) removing the side chains from the completed natural molecule
What are the 2 classes of semisynthetic penicillins? How do they differ? what do they have in common? Give examples of each?
2 classes of Semisynthetic penicillins:
1. Narrow spectrum, only Gram-positive, but RESISTANT to penicillinase (ex: Oxacillin)
2. Extended spectrum, many gram-negatives (ex: Ampicillin)
How are penicillins generally modified to increase their resistance to Beta-lactamases?
Addition of BULKY side chain that statically hinder beta lactam ring access
What are Extended-spectrum penicillins? What are the different classes?
Extended-spectrum Penicillins
-Semi-synthetic penicillins effective against many gram-negative Bactria as well as gram-positive bacteria
-NOT RESISTANT to penicillinases
-Different classes produced over the years. a broader spectrum of activity achieved with each group (listed in order)
-Aminopenicillins (ampicillin and amoxicillin)
-Carboxypenicillins (carbenicllin)
-ureidopenicillins (mezlocillin anda azlocillin)
What modifications increases outer membrane permeability ?
Less bulky side groups and additional hydrophilic polar groups allow passage through porins (permeability)
What is the role of Beta-lactamase inhibitors? Who produces it?
Beta-Lactamase Inhibitors
-*A strategy to overcome penicillinases is to combine penicillins with potassium Clauvanate *
-produced by Streptomycete
-Irreversible inhibitor of Beta-lactamase (suicide inhibitor)
(will irreversibly bond to b-lactam ring)
-Despite having a Beta-lactam ring, it has negligible intrinsic antimicrobial activity
What does MRSA stand for? How did it develop? What is used for now?
MRSA (methicillin-Resistant Staphylococcus aureus) (MRSA)
1. Staphylococcal infections rapidly became resistant to Penicillin due to plasmid-borne Beta-lactamase gene
2. semisynthetic penicillin antibiotics relatively resistant to Beta-lactamase (ex; methicillin ) are introduced
3. S. aureus strains resistant to methicillin appeared, and were termed MRSA
-resistance is so common that methicillin use has been discontinued in the US
-MRSA is now applied to describe S. aureus strains that have developed resistance to 1) other penicillin resistant penicillins, 2) penicillin combined with beta-lactamase inhibitors and 3) cephalosporins
*resistant to many of the antibiotics used to treat ordinary staph infections
Provide the complete phrases for the acronyms MRSA, VRSA, and VRE,
and discuss the usage of these acronyms with respect to increasing
antibiotic resistance.
Come back to this
MRSA (methicillin-resistant Staphylococcus aureus)
-gain resistance to methicillin (penicillin that was resistant to b-lactamase)
- VRSA (Vancomyisn-resistant S. aureus) and VRE (vancomycine-resistant Enterococcus) that formed due to widespread use of Vancomycin (antibiotic)
