Antimicrobial Drugs Flashcards
(119 cards)
1
Q
What is selective toxicity/”magic bullet” ? Who popularized this concept?
A
Selective toxicity/”magic bullet”: the idea of a drug killing pathogens without damaging the hosts
concept popularized by Paul Ehrlich
2
Q
What is Chemotherapy? Who coined this term?
A
Chemotherapy: the use of drugs/chemicals to treat Any disease (broad historical term coined by Paul Ehrlich) - Antimicrobial chemotherapy
3
Q
What are antimicrobial drugs?
A
Antimicrobial drugs: compounds that interfere with the growth of microbes within a host
4
Q
What is an antibiotic ?
A
Antibiotic: A substance produced by a microbe that in small amounts, Inhibits another microbe (struck definition in text for ch. 20 )
5
Q
Are sulfa drugs antibiotics? Is ampicillin an antibiotic ?
A
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)
6
Q
What is definition of antibiotic using glossary of textbook?
A
Given in glossary of textbook, an “antimicrobial agent, usually produced naturally by a bacterium or fungus”
7
Q
What was the first antibiotic discovered? Which scientist were invivled>
A
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.
8
Q
what is an antibiotic class?
A
Antibiotic class: a grouping of related antibodies
9
Q
What has occurred in amount of antibodies over time?
A
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
10
Q
Explain why pharmaceutical companies put very little investment in the developmental of new antibiotics?
A
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
11
Q
What is Antibiosis? what mediates it?
A
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
12
Q
How many species in environment are uncultured?
A
Approximately 99% of ALL species in external environment are uncultured
13
Q
What is ICHIP ? Why is it useful? What bacterium can be identified using the method?
A
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
14
Q
Explain the process of ICHIP. What occurs?
A
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)
15
Q
What types of microbes produce most antibiotics?
What are other microbes that produce antibiotics
A
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
16
Q
Which genus produces more than half of our antibiotics?
A
STREPTOMYCETES
17
Q
What are two characteristics doo almost all antibiotic producing microbes have in common
A
They all produce SPORES
-They live in SOIL
18
Q
Differentiate between broad spectrum antimicrobials and Narrow-spectrum antimicrobials
A
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)
19
Q
Recognize that different drugs can be classified as antibiotics depending
on how “antibiotic” is defined
A
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
-
20
Q
what is the advantage and disadvantage of treating a bacterial infection with a broad spectrum antibiotic?
A
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
21
Q
What are the two definitions for superinfection ?
A
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
-
22
Q
Why are the two organisms( Clostridium difficile and Candida albicans) not affected by initial antimicrobial treatment?
A
Because they are naturally RESISTANT to antibiotics
23
Q
How can antimicrobial drugs be classified as?
A
Antimicrobial drugs are classified as either Bacteriocidal or bacteriostatic
24
Q
Differentiate between bactericidal and bacteriostatic
A
Bactericidal: Kills microbes directly
Bacteriostatic: prevent microbes from growing
-Host’s defenses (antibody production and phagocytosis) usually destroy organisms
25
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
26
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
27
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
28
What is a common antimicrobial target in fungal plasma membranes?
STEROLS
29
Why does penicillin only affect actively growing cells?
because only peptidoglycan synthesis is targeted
30
Why do antimicrobials that target replication and transcription generally have limited medical usefulness?
because most also interfere with mammalian DNA/RNA
31
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
32
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
33
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.
34
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.
35
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
36
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
37
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)
38
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
39
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
40
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
41
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)
42
How are penicillins generally modified to increase their resistance to Beta-lactamases?
Addition of BULKY side chain that statically hinder beta lactam ring access
43
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)
44
What modifications increases outer membrane permeability ?
Less bulky side groups and additional hydrophilic polar groups allow passage through porins (permeability)
45
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
46
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**
47
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)
48
What are Carbapenems? Why do they have broadest spectrum of activity of Beta-lactam antibiotics? What is Imipenem and its role? How is impanel degraded?
Carbanpenems:
-Class of Beta-lactam antibiotics with a C replacing a S and introduction of DOUBLE BOND in the common penicillin nucleus (carbon is replaced with sulfur that was in orig penicillin )
-Broadest spectrum of activity of Beta-lactam antibiotics ; because thy are taken up by a selective porin (basic amino acids)
(active against 98% of hospital patient isolated organisms)
-Resistant to penicillinases, but carbapenemases have arisen
-Imipenem is a semi-synthetic representative of the group . Is effective alone or can be given with cilastatin
-Imipenem is degraded in the kidneys by dehydropeptidase and its activity can be prolonged by combining with cilastatin
49
What are Monobactams? What are its characteristics? What is an example of one?
Monobactams
-Class of Monocyclic Beta-lactam antibiotics
-produced by several bacterial species, but Aztreonam is a chemically manufactured version (considered synthetic) and is the ONLY monobactam used clinically
-Activity limited to certain gram-negative bacteria because it partly binds to the penicillin binding proteins of gram positive and anaerobic Bacteria)
50
What are the characteristics of Cephalosporins ? How do they differ from penicillin ? How are they similar?
Cephalosporins:
-Beta-lactam ring structure matches penicillin
-First generation spectrum of activity matches natural penicillin
-Although portions of the common nucleus differ from penicillin, b-lactamases have arisen that inactivate them
(cephalosporin have double bonded hexane ring)
51
Where did Cephalosporins develop from?
Cephalosporins were developed from cephalosporin C, a natural product of Cephalosporium acreminium
52
Describe how cephalosporins are grouped and how this affects the beta-lactamase resistance ? What is the most extended generation? Which generation does not have gram negative coverage ? Which is active against MRSA and E. faecalis
Cephalosporins
-A very extensive class grouped by GENERATIONS, which reflect Increased gram-negative coverage as development continued:
(Beta-lactamase resistance also increases in most generations)
-First generation: Narrow spectrum, GRAM POSITIVE
-Second generation: Extended spectrum includes some gram-negative
-Third generation: increased gram-negative spectrum, includes some Pseudomonads
-Fourth generation: most- extended spectrum of activity
-fifth generation: also active against MRSA (methicillin-resistant S.auresu) and E. faecalis
53
differentiate between the structures of the Beta lactam antibiotics (Penicillin, monobcatam , cephalosporins, carbapenem) ?
Beta lactam Antibiotics:
1. Penicillin: beta lactam + 5-membrerd Thiazolidinie ring (sulfur, cooH)
2. Monobactam: Monocyclic beta lactam ring (r groups)
3. Cephalosporins : Beta + 6-membered Dihydrothiazine ring (double bond hexane ring, with R group)
4. Carbapenem: Beta lactam + unsaturated 5 membered ring and susbstiution of carbon for sulfur at C1
(similar to penicillin structure, but s replaced with C; double bond in pentane)
54
What are the major polypeptide antibiotics
(polypeptide bacterial cell wall inhibitors) ?
Bacitracin and Vancomycin (they are both narrow spectrum; gram positives)
(they also prevent NAG and NAM entry)
55
What is the structure and function of Bacitracin? What kind of antibiotic is it? How is it used? What kind of spectrum does it have?
Polypeptide antibiotics
*Bacitracin
-MIXTURE of related cyclic polypeptides from Bacillus subtitles isolated from infected compound fracture from a girl named Tracy
-interferes with the transport of peptidoglycan precursors (NAG, NAM monomers) across the cytoplasmic membrane
-use almost always restricted to topical application (TOXIC orally)
-Narrow spectrum (gram positives)
(ribosomes are NOT involved in the synthesis of bacitracin)
56
What are the characteristic for Vancomycin? What is its structure and function? What kind of antibiotic is it? How does it related to Teixobactin? What has its widespread use led to?
Polypeptide Antibiotics
*Vancomycin;
-named for the word "Vanquish" (vanquished MRSA)
-Traditionally used as a drug of last resort against antibiotic resistant S. aureus (MRSA)
-Binds NAG-NAM subunits and prevents their incorporation into the peptidoglycan matrix (same target as Teixobactin but different mode of action)
-Glycopeptide derived form Streptomyces
-Widespread use has led to the appearance of Vancomycin-resistant Staphylococcus aureus (VRSA) and Vancomycin resistant Enterococcus (VRE)
-Both vancomycin and Teixobactin ar Narrow Spectrum (gram positives)
(vancomycin structures has many benzene rings with double bond)
57
What are the major Antimycobacterial antibiotics ?
Isoniazid (INH) and Ethambutol
58
What are the characteristics of isoniazid? What kind of antibiotic is it? How it used? How is used to treat Tuberculosis?
Antimycobacterial antibiotics
-Isoniazid (INH)
-INHIBITS mycolic acid synthesis
-synthetic drug never used on its won to treat tuberculosis because resistance quickly develops
-Used with Rifampin (rifampicin) and or ethambutol (different regimens employed to treat TB)
(structure: benzene ring, with amino)
59
What do Isoniazid and Ethambutol have in common?
Both Isoniazid and Ethambutol are antimycobacterial antibiotics . They are both synthetic drugs used in combination with each other to treat Tuberculosis . They are also both weak drugs (slow growth of organisms)
60
What is the role of Ethambutol? what are other characteristics?
Polypeptide antibiotics
-Ethambutol: *inhibits incorporation of mycolic acid into the cell wall*
-comparatively Weak synthetic antitubercular drug that is used as a secondary drug to reduce resistance problems
61
What are the classes of protein synthesis of inhibitors ?
Classes of Protein Synthesis inhibitors
1. Chloramphenicol
2. Aminoglycosides
3. Tetracyclines
4. Macrolides
5. Streptogramins
6. Oxazolidinones
62
Describe how each of classes of protein synthesis inhibitors actually inhibit protein synthesis
The inhibition of protein synthesis By Antibiotics
(4 classes)
-Streptomycin: changes shape of 30S portion, causing code on mRNA to be read incorrectly (make translational mistakes)
-Chloramphenicol : binds to the 50S portion and Inhibits formation of peptide bond
-Tetracyclines : interfere with attachment of tRNA to mRNA-ribosome complex
-Macrolides: block polypetide exit tunnel
63
Discuss characteristics of Chloramphenicol ? What kind of antibiotic is it? What is its function and structure?
Inhibitors of protein synthesis:
*Chloramphenicol (more than 40 trade names)
-LOW cost: simple structure acne be chemically synthesized rather than isolated from Streptomyces
-Broad Spectrum (gram + and - )
- *Binds to 50S subunit: Inhibits peptide bond formation *
-Chlroamphenicol and *metronidazole* have potent ANAEROBIC activity
(does not act at ribosome)
64
Does oxygen influence antibiotic acitivity?
YES, Oxygen is required for the uptake of amioglycosides
65
Discuss the characteristics of Aminoglycosides ? What is the structure and function? what kind of antibiotic is it> How are they used?
Inhibitors of Protein Synthesis
*Aminoglycosides (amino acids linked by glycosidic bonds)
-Streptomycin, Neomycin, Gentamicin, Tobramycin (4 representative members)
- *Gram-NEGATIVE spectrum- but NOT anaerobes*
-Changes shape of 30 S subunit causing translation errors
-althoiugh they have side effects, and resistance has developed, they are still *The MOST USED Antibiotics used WORLDWIDE *due to their High efficacy can low cost
(6 ring structure)
66
Why is Gentamicin spelled with an I ?
Gentamicin is spelled with I due to it being derived from *Micromonospora species *
The Aminogylcosides that are derived from bacteria Streptomycin are given name---> ycin
those that are derived from micromonospora are spelled icin
67
What are characteristics of Tetracyclines? What is the function and structure ? Which are the natural tetracyclines? What are the disadvantages of using it for treatment ?
Tetracyclines
-Broad spectrum (gram + and gram -)
-*Bind to 30S ribosomal subunit and interfere with tRNA-codon attachment *
-Natural tetracyclines are produced by Streptomyces and include tetracycline, chlortetracycline, and oxytetracycline
Semisynthetic tetracyclines (ex; doxycycline) have longer retention times in the body
-Selective toxicity due to both greater bacterial ribosome sensitivity and poor penetration Into mammalian cells
-However, still valuable against intracellular pathogens
Treatment advantages: Suppress normal microbiota, may brown children's (< 8 years) teeth, or cause liver damage in pregnant women
(4-ring structure)
68
What are the characteristics of Macrolides. what is the structure and function? What is the first member of this class?
Macrolides
-named for presence of a macrocyclic lactone ring
-*Binds 50S subunit; prevents translocation by blocking the Exit tunnel*
-Natural and first member of this class if erythromycin
-similar spectrum to Penicillin G (can't penetrate gram- negative LPS) but can be taken ORALLY
-Newer semi-synthetic members are derived from erythromycin have a broader spectrum
69
What are characteristics of Streptogamins? What is its structure and function? How are they used for treatment ?
Streptogamins:
-Cyclic peptides
-Gram positive spectrum
-The only approved streptogramin , is a mixture of two-streptogramins (quinupristin, and dalfopristin) proudced by Streptomyces species
-These streptogramins act synergistically at TWO uniquely different points on 50S ribosomal subunit, which together causes premature protein termination
-dalfopristin blocks an EARLY translational step
-quinopristin blocks as LATER translational step
-Major clinical use is treatment of Gram-POSITIVE infections, particularly VRSA (Vancomycin-resistant Staphlyococcus aureus), and Vancomycin-resistant Enterococcus (VRE)
70
What is the role of Oxazolidoinones? What is its function? What member is a part of this group?
Oxazolidinones
-FDA approved in 2001
-it is a synthetic antimicrobrial, which may lessen resistance rate (b/c it binds linezolid?)
-It has unique target and mechanism- prevents formation of a functional 70-S initiation complex by binding the 50S subunit near 30S interface
- Linezolid is a member of this group
-its spectrum is limited to gram-positives but effective against certain Streptococci and Enterococci resistant to quinuprisin and dalfopristin
71
What is the role of Linezolid? What class of protein synthesis inhibitors is a part of?
Linezolid binds to the 50S subunit, which prevents the formation of a fuctional 70S initiation complex
Linezolid a member of Oxazolidinoes (protein synthesis inhibitor)
72
Which antibiotics are part of the plasma membrane inhibitors ?
Plasma membrane inhibitors:
*Some antibiotics target fatty acid biosynthesis
-isonizaid
-triclorosan
-Platensimycin
*other antibiotics target the formed membrane
-Polymxin B
73
Which antibiotics target fatty acid biosynthesis ? What class of antibiotics are they apart of? What is their function ?
Plamsa membrane inhibitors:
some antibiotics target fatty acid biosynthesis
-Isoniazid (mycolic acid synthesis)
-triclorosan (household antmicricrobial that inhibits a fatty acid biosynthetic pathway enzyme (Fabl)
-platensimycin (a new chemical class (2006) of natural antibiotics delayed preclinical trials due to elevated levels necessary for effectiveness)
*Blocks two different enzymes in fatty acid biosynthesis (FabB and FabF).
74
What is the weakness of targeting fatty acid biosynthetic pathway to kill pathogens?
REVIEW
75
Distinguish between Type I and Type II fatty acid synthetases
Type I Fatty acid synthase; multifunctional polypeptide in mammals and yeast (Have one large enzyme that does all activities)
Type II fatty acid synthase: found in prokaryotes, plants, fungi, parasites and mitochondria (invidividual enzymes carry out different activities)
76
Discus the other antibiotics that are part of Plasma membrane inhibitor? What is it structure and function ? how is it used clinically?
Plasma membrane inhibitor (or injury)
-Other antibiotics target the formed membrane
*Polymyxin B (natural peptide antibiotic from bacterium
Bacillus polymyxa
-binds LPS of gram-negative bacteria, then alters both inner and outer membranes, making them more permeable
-Little to no effect on gram-positives, since thicker cell wall prevents access to membrane
-applied topically
-combined with bacitracin and neomycin in an over-the-counter antiseptic cream "Neosporin"
77
What are the Nucleic Acid synthesis inhibitors ?
Rifamycin and Quinolones, and Fluoroquinolones
78
What are the characteristics of Rifamycin. What kind of antibiotic is it? Describe the structure and function. How is it used clinically?
Inhibitors of Nucleic Acid Synthesis:
*Rifamycin
Members are produced naturally by the bacterium Amycolatopsis mediterranie, or artificially
-Broad spectrum
-inhibits transcription by binding prokaryotic RNA polymerase
-*Semisynthetic Rifampin/Rifampicin is the best-known family member*
-key use as part of the antibiotic cocktail for treating Mycobacterium infections, including tuberculosis and leoprosy
79
What are the characteristics of Quinolones and fluoroquinolones? What kind of antibiotics are they? What are their structure and functions and how are they used clinically?
Inhibitors of nucleic acid synthesis :
*Quinolones:
-family of synthetic broad-spectrium antibiotics
-INHIBITS DNA GYRASE
-first member of Nalidixic acid (early 1960s)
-historically used to treat urinary infections, but members are RARELY used to day, since naxludic acid listed as carcinogen in 1998. Led to
forming of:
*Fluoroquinolones:
-fluorinated quinolones
-divided into generations based on progressively broader spectrum of activities
-group is relatively non-toxic, but resistance can develop rapidly even during treatment (b/c DNA gyros can easily pick up mutations that their compounds cannot affect)
-treatment of choice for unitary tract infections
80
What is the role of Sulfa drugs like Sulfonamides? What do they inhibit ? What are the characteristics ? What is the most-widely used sulfa drug and what does it include?
Inhibiting synthesis of essential metabolites
*Sulfonamides (sulfa drugs)
-among the first synthetic antimicrobial drugs
-structurally similar to para-aminobenzoic acid
- Interfere with conversions of PABA to folate (sulfonamide are competitive inhibitors )
- Bacteriostatic (inhibit microgbiral growth)
-Broad spectrum
-Most widely used sulfa drug is used as a combination of the sulfonamide called Sulfamthoxaozle with trimethoprim (TMP-SMZ)
81
What is an example of drug synergy? Explain how this works and how Sulfa drug combines with trimethoprim. what is the benefit of combining this drug?
An example of drug synergy (TMP-SMZ)
sulfamteoxazole combining with trimethoprim
-process
1. SMZ, a sulfonamide that is structural analog of PABA, competitively inhibits the synthesis of dihydrofolic acid from PABA
2. Trimethoprim, a structural analog of a proton of dihydrofolic acid, competitively inhibits the synthesis of tetrahydrofolic acid
in combination, only 10% of the concnetration is needed, relative to individual use
-Comnbination (TMP-SMZ) also yields BROADER spectrum an DECREASED resistance
82
Why are only bacteria affected by sulfa drugs?
Only bacteria are affected by sulfa drugs because we humans get our folate from our diet and don't need the drugs. With bacteria, they have to synthesize folic acid on their own, since the folic acid (vitamin) is too big to enter bacterial cell.
83
What are the major Antifungal drug targets?
Antifungal Drug targets
-Fungal sterols
-fungal cell walls
-Nucleic Acids
-Other fungal targets
84
What are the modes of actions of the different antifungal drugs?
Modes of action for Antifungal drugs
-Inhibit DNA and RNA synthesis: Flucytosine
-Disrupt microtubule function: griseofulvin
-Disrupt membrane; polyenes
-Inhibit synthesis of Beta (1--> 3) glucans: echinocandins
-inhbit ergosterol synthesis: imidazole, triazole, allyamine
85
What is the principle fungal sterol? what is this strucutue called in humans? Which antifungal drug groups target the fungal sterol?
Fungal sterols
-The principal sterol in fungal plasma membrane is Ergosterol (cholesterol in humans)
-Several antifungal drug groups TARGET ergosterol
1) polyenes
2) Azoles
3) Allylamines
4) Thiocarbamates
86
What is function of polyenes and how does it target ergosterol? What is a common member ?
Polyenes target ergosterol (fungal sterol)
-polyenes; (polyunsaturated organic acids)
-Amphotericin B, produced by Streptomyces is the most commonly used member
- it binds to ergosterol and forms a transmembrane channel that leads to leakage
(hydrophobic part of member binds to ergosterol; forms aqueous pore promoting leakage)
87
How do Azoles target fungal sterols (like ergosterol) What are the antifungal drugs that do this and how are they each used differently (Clinically)
2) Azoles
synthetic class that inhibit ergosterol synthesis
-contains some of the most widely used antifungal drugs
-imidazoles (*miconazole*, clotrimazole, ketoconazole, etc) are commonly used topically without prescription for localized surface infections (ex; athletes foot and vaginal yeast infections )
-Triazoles: (*Fluconazole*, voriconazole, etc) are used for invasive-life threatening fungal infections
88
What are azoles?
Azoles : a class of five-membered nitrogen heterocyclic ring compounds containing at least one other non-carbon atom of either nitrogen, sulfur or oxygen.
89
Explain how allylamines and thiocarbamates target Fungal sterol (like ergosterol) What is a representative member? How is it used clinically?
3) Allylamines target fungal sterol (ergosterol)
-they inhibit a different enzyme (than the azoles) in the ergosterol biosynthetic pathway
-Terbinafine is a representative member
-Common over-the counter alternative to miconazole as a topical treatment for athletes foot.
4) Thiocarbamates
-inhibits the SAME enzyme as allyamines
-Tolnaftate is a representative member
-common over-the counter alternative to miconzaole as a topical treatment for athlete's foot
90
What do miconazole, allylamines, and thiocarbamates have in common. How are allylamines and thiocarbamates similar ?
Miconazole, allylamines and thiocarbamates are both used topically to treat athlete's foot
-Allylamines and thiocarbamates, since they both inhibit the same enzyme in ergosterol pathway, and are both used as topical treatment for athlete's foot
91
What are fungal cell walls composed of? Name the anti-fungal class and drug that targets fungal cell wall synthesis
Fungal cell walls are composed of a tight, semipermeable fibrous network polymers such as chitin, Beta-glucan, other polysaccharides and mannoproteins
-Beta-glucan is a primary drug target
-The *Echioncnadin* class of antifungals (produced by fungi) inhibits the enzyme 1, 3 beta-glucan synthase
-A member of this group , *Caspofungin* is commercially available (others are in developoment)
92
What is the composition of the Yeast cell wall ? what are other components of cell?
Yeast cell wall composed of:
-oligosaccharide
-mannoproten
-Chitin
-Glucan
(The periplasmic place of yeast is made of periplasmic enzymes )
Yeast cell also has plasma membrane and integral protein)
93
What is the structure and function of Flucytosine? What is the target? Do mammalian cells have flucytosine ?
Flucytosine Targets Fungal NUCLEIC ACIDS
-Flucytosine is a synthetic analog of pyrimidine cytosine (prodrug)
-in fungi, flucytosine is converted to 5-floururacil--> 5-FUMP---> 5-UTP
-5-UTP can be incorporated into RNA and INHiBIT translation, or be further metabolized into 5-FdUMP, a potent inhibitor of thymidate synthase and thus DNA synthesis
(hence flucytosine inhibits DNA and RNA synthesis)
-Mammalina cells LACK the flucytosine converting enzyme
(structure of flucytosine; change Amon group from amino to double bond to o in fluorouracil)
94
What are the other antifungal drugs that do not target ergosterol synthesis (fungal sterol) or fungal cell wall synthesis? What are their own targets and how do they work?
Other antigungal drugs
1) Griseofulvin binds to fungal tubulin interfering with microtubule assembly and subsequently mitosis . Produced by species of Penicillium
2) Undecylenic is an organic unsaturated fatty acid. Activate against athlete's foot but NOT as effective as tolnafate, terbinafine, or miconazole . Mechanism of action is unknown
3) Pentamidine is used to treat pneumocystis pneumonia a complication of AIDS (caused by a fungi called Pneumocytosis jirovecci) Mechanism of action unknown
95
Describe the incidence of antiviral drugs? what are the non-HIV antivirals vs the HIV targeted antivirals ?
Antiviral drugs
-Viral infections are common but few antiviral drugs have been approved and most are only effective against a restricted group of diseases
-in developed countries, 60% of infectious diseases are caused by viruses
-at least 90% of U.S. population suffers from viral disease each year
Non-HIV antivirals
-Nuclesodie and nucleotide analogs
-Other enzyme inhibitors
-Interferons
HIV-targeted antivirals
-Reverse transcription
-protease inhibitors
-cell entry inhibitors
-integrase inhibitors
96
What is the role Acyclovir? What kind of drug is it? What is it used to treat?
Nucleoside and Nucleotide analogs
Acyclovir (non-HIV antiviral drug)
*Acyclovir structurally resembles the nucleoside dexoyguanosine*
-generally useful for treating herpesvirus infections
Several other nucleoside and nucleotide analogs are commercially available
(acyclovir does not have sugar that is in dexoygunasoine)
97
Explain the mechanism of action for antiviral drug Acyclovir ? What makes it effective?
Acyclovir is a pro drug.
in a normal cell, not infected by virus and has normal thymidine kinase, Acyclovir will NOT have effect on cell.
The thymidine kinase will combine phosphate with nucleoside to form nucleotides, which are incorporated into DNA.
* in a virally infected cell, the thymidine kinase is altered and converts the acyclovir (analog of dexoyguanosine) to a FALSE NUCLEOTIDE, which blocks DNA synthesis by DNA polymerase.
-Acylo-GTP is incorporated into viral DNA , resulting in chain termination
-*Acyclovir is effective ONLY against herpes group viruses that produce their own specific thymidine kinase.*
98
Discuss the characteristics of Thymidine kinase? How m any nucleosidse can viral thymidine kinase phosphorylate ?
Host cell thymidine kinase is very specific to thymidine, since the cell has other enzymes to phosphorylate the other nucleotides. (ex deoxyguanosine kinase_
The viral thymidine kinase can phosphorlaye FOUR nucleotides
99
Which antifungal drugs inhibit enzymes? Which enzyme is inhibited?
Zanamivir and oseltamivir inhibit the enzyme neuraminidase of influenza virus
(these enzymes inibitr drugs are non-HIV drugs)
100
What is the role of interfoerons? Which are used as drugs? How can interferons be stimulated ?
Cells produce interferons to PREVENT the spread of viruses to new cells
-*Alpha interferon, drug of choice for viral hepatitis* (first tested in 1978, human recombinant protein in E. coli)
-Interferon production can be stimulated with the drug imiquimod
101
Describe the HIV antivirals and their mode of action, and targets?
HIV antivirals
* Block cell entry*
-Drug targeting the host cell CCR5 receptor used for viral entry
-syntheitic peptide that inhibits fusion by mimicking a region of the gp41 HIV-1 envelope protein
*Reverse transcription inhibitors*
-nucleside (axiodthymindine/AZT) and nucleotide (tenofovir) analogs Thymidine and adenosine chain terminators respectively.
non-nucleoside agents (inhitbis reverse transcriptase)
*Integrase inhibitors*
-inhibi the enzyme that integrates viral DNA into genome of infected cell
*Protease inhibitors*
-analogs of sequences present in processed proteins (competitive inhibition )
* These HIV antivirals are especially effective WHEN COMBINED*
102
What are the antiprotozaon drugs? What are their targets and how are they produced?
Antiprotozaon Drugs
*Quinine
-isolated from cinchona tree
-*used to treat MALARIA *
-mechanism of action not fully resolved
-now largely replaced by synthetic derivatives used to treat a variety of protozoan and amoebic diseases
*Metronidazole (prodrug)
-Selective for *ANAEROBIC bacteria and protozoa*, due to their ability to intracellularly reduce metronidazole to its active form. *Reduced metrondizaole covalently binds to DNA and disrupts synthesis *
103
Describe how tests are used for antimicrobial effectiveness ?
Tests for antimicrobial effectiveness
-in clinical practice, antibiotic are most frequently prescribed based on general guidelines and knowledge about sensitivity
-however, since many bacteria are known to be resistant to several classes of antibiotics, treatments is NOT always straight-forward. Different microbial species and strains have different degrees of susccpetibilty which can change with time during therapy
104
What is the use of Kirby Bauer Test? What kind of method is used? what does it test? What are advantages and disadvantages?
The Disk-Diffusion method
-Kirby Bauer Test: antibiotic sensitivity
-The diameter of the zone of inhibit is measured.
*In general, the larger the zone, the more sensitive the microbe
(this is not always true because zone of clearing deepens on how well it diffuses on disk)
-Zones can be compared to a chart of other bacteria and judges as either sensitive, intermediate or resistant
-Although cheap and easy, results are often inadequate for clinical purposes
(charts-- are organism specific)
105
What is the The E (Epsilometer) Test
The E (Epsilometer) TEst
-a gradient diffuse method that determines the antibiotic sensitivity and estimates MIC (minimal inhibitory concentration)
-Plastic strips placed on a lawn of cells containing an increased gradient of the antibiotic.
106
What is the role of Broth Dilution Test? What does it test? What is the resistance for drugs doxycycline, streptomycin, Sulfamethoxazole, Streptomycin, Ethambutol and kanamycin?
Broth dilution test: technique used to determine MIC (minimal inhibitory concentration)
-technique occurs by holding identical volumes of broth with antimicrobial solution in incrementally, increasing concentrations, and are inoculated with a known number of bacteria.
- it determines the lowest concentration of the assayed antimicrobial agent (minimal inhibitory concentration, MIC) that, that inhibits the visible growth of the bacterium being investigated.
Doxycycline: (growth in all wells, hence bacteria resistant to antibiotic)
Sulfamethoxazole (trailing end point;usually read where estimated 80% reduction growth; less resistant)
- Streptomycin (NO growth in any well; Sensitive at all concentrations (drug is effective, and will kill bacteria)
-Ethambutol and Kanamycin (growth in fourth wells; EQUALLY sensitive to ethambutol and kanamycin)
(Decreasing cocentraton of drug in container goes from left to right)
plates with media/drug concentration can be purchased frozen or freeze dried.
107
How can the minimal bactericidal concentration (MBC) be determined from the previous test?
Wells lacking growth are cultured in broth/agar plates that lack the drug. Growth will occur if drug is not bactericidal
108
Why it important to know MIC/MBC?
to avoid antibiotic over usage- since it is expensive and cause potential toxic side effects
MIC: minimal inhibitory concentration: lowest cocentarion of antimicrobial drug that inhibit growth of bacteria
MBC: minimal bactericidal concentration : Lowest concentration of antibacterial agent that kill bacteria
109
What is an antibogram?
Antibiogram- summary report of antimicrobial suscepbitliy testing data from patients. Microbes isolated form patients are tested for susceptibility against a battery of antimicrobial drugs.
in hospitals, these results cane consolidated to guide antibiotic selection and detect emergence of antibiotic resistant strains (geographic source, and whether community or hospital unit specific acquired is important)
(in county wide antibiogram: the number of isolates tested and susceptible percentages0.
-suspecibility percentages:
Green > 90%
yellow- 60-90%
-Orange- less than 60%
110
Describe the steps to how one can resistance to antibiotics
resistance to antibiotics
-1. Blocking entry (of antibiotic)
2. Inactivating enyzmyes
3. Alteration of target molecule
4. Efflux of antibiotic
111
Further elaborate, and describe the mechanism of Antibiotic resistance
Mechanisms of Antibiotic Resistance:
1. Prevention of drug penetration
-gram-negative cells are in inherently more resistant to antibiotics. The outer membrane. provides a barrier which restricts access to porins
-porin mutations can further restrict antibiotic entry to perisplamsic space
2. Enzymatic destruction or inactivation of drug
-nearly 200 beta-lactamases known
-other types of inactivation (chloramphenicol , amiogylcosides)
3. Alteration of drug's target site
-rpsL (protein found in bacterial ribosome; target for streptomycin)
-another penicillin binding protein (PBP)
-MRSA (express a foreign PBP that is unaffected by methicillin
-4. Rapid efflux of drug
-pumps present in plasma membrane of gram-negative ebacteira
confers resistance to all major classes of antibiotics
other mechanisms:
-produce large amount of target enzyme/molecule
-produce less of target enzymes/moelcuel (ex: polyene antibiotics and sterols)
Resistance genes are on plasmids or transposons that are transferred between bacteria
112
What is the consequence of antibiotic misuse?
Antibiotic m issue selects for resistance mutants
-misuse includes
-using outdate, impure or counterfeit antiibiotics
-using antibiotics for common cold and other inapprotapte condition
-acute problem in may less-developed countries where antibiotics can be purchased without prescription
-misuse in U.S for 30% of ear infections, 100% common cold, 50% of sore throats, the antibiotics prescribed are innappropriate to treat pathogen
Using antibiotics in animal feed
-failing to complete prescribed regimen
-using someone's else leftover prescription
113
What is synergism and antagonism ?
Synergism: occurs when the effect of two drugs together is GREATER than the effect of either alone
Antagonism: occurs when the effect of two drugs together is LESS than the effect of either alone
(Disk with anitbioitic amoxicillin-clavaulanic acid has clear (synergistic inhibition ) (combo of drugs will inhibit growth of bacteria)
(disk with antibiotic aztrenoam has area of growth (cloudy)
114
Explain how tetracycline sometimes interferes with activity of penicillin
tetracycline is bacteriostatic: stops the growth of bacteria
But the action of penicillin REQUIRES bacterial growth
115
What is Therapeutic Index? What does it assess? What is the equation?
Therapeutic index; a comparison of the amount of therapeutic agent that produces the therapeutic effect to the amount that causes Death.
The therapeutic index is often defined in terms of comparison of AVERAGE TOXIC DOSE vs Average EFFECTIVE Dose
TI (therapeutic index) = TD50/ED50.
A HIGHER index is preferable to a lower one.
116
Describe why prescribing multiple drugs can be problematic
Two drugs can be safe alone, but cause toxic effects in combination (average senior citizen is on SEVEN pharmaceutical drugs)
-one drug may neutralize the effect of another (ex: some antibiotics/contraceptive pills)
-individuals may be hypersensitive to some antibiotics
117
What are new chemotherapeutic agents that have been researched ?
New chemotherapeutic agents:
1) Antimicrobial peptides
2) Phage therapy
118
What is the role of Antimicrobial peptides? Describe its mechanism of action.
1) Antimicrobial peptides
-part of inmate immune systems of higher organisms
-generally 100 amino acids or less and carry a POSITIVE charge (cationic peptides)
- mechanisms of action
**-most disrupt microbial and viral enveloped membranes rich in anionic phospholipids (PRIMARY Target) **
-a variety of other targets
119
What is phage therapy? how is its used?
2) Phage therapy
-use of bacteriophages to treat pathogenic bacterial infections. Although used and developed mainly in former Soviet Union countries for more than 50 years, still being tested elsewhere. Theoretically, could specifically target bacterial cells. Generally used in the US as a last-ditch effort after antibiotics fail.
June 2018- 1st phage therapy center in North America at UCSD ( University of Californina, San Diego) school of medicine
