Transcript Foundations in Microbiology

Drugs, Microbes, Host – The
Elements of Chemotherapy
Chapter 12
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*How you should approach this chapter…
1. Antimicrobial chemotherapy and antimicrobics
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What are selection criteria?
How are they used?
What are adverse effects?
HOW DO THEY WORK (what is their mode of
action)?
Blocks or inhibits:
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Cell wall synthesis
cell membrane structure/function
nucleic acid structure/function
protein synthesis
(Specific metabolic pathways)
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2. Antibacterial drugs: Antibiotics and
Synthetics (what is the difference?)
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Classes/categories; know: source, mode of
action, application/spectrum
Antibiotics: penicillins, cephalosporins, other
B-lactam Abt, aminoglycosides, tetracyclines
and other Streptomyces antibiotics, Bacillus
antibiotics, other new drugs
Synthetics: sulfonamides, flouroquinolones,
others (narrow and broad spectrum)
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…continued
3. Other antimicrobials (time permitting…) :
(antifungals, antiprotozoal, anthelminthics,
antiviral).
4. Drug resistance – How? Why? Effect?
5. Side effects of drugs – toxicity, allergy,
superinfection
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Origins of antimicrobial drugs
_____________ are common metabolic
products of aerobic spore-forming bacteria &
fungi.
 bacteria in genera Streptomyces & Bacillus
 molds in genera Penicillium &
Cephalosporium
By inhibiting the other microbes in the same
habitat, antibiotic producers have less
competition for nutrients & space.
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Selectively toxic
Drugs should kill or inhibit microbial cells
without simultaneously damaging host
tissues.
As the characteristics of the infectious
agent become more similar to the
vertebrate host cell, complete selective
toxicity becomes more difficult to achieve
& more side effects are seen.
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Targets of antimicrobial drugs
1. Inhibition of _____________ synthesis
2. Disruption of _____________ structure
or function
3. Inhibition of _____________ synthesis,
structure or function
4. Inhibition of _____________ synthesis
5. Inhibition of other metabolic pathways
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The Spectrum of an Antimicrobic Drug
Spectrum – range of activity of a drug
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_____________ _____________ – effective on a
small range of microbes
Target a specific cell component that is found only in
certain microbes
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_____________ _____________ – greatest
range of activity
Target cell components common to most pathogens
(ribosomes)
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1. Drugs that affect the bacterial cell wall
_____________(and derivatives) and
cephalosporin block synthesis of
peptidoglycan, causing the cell wall to
lyse.
Other drugs include: vancomycin,
bacitracin, monobactams, fosfomycin,
cycloserine, isoniazid
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2.Drugs that disrupt cell membrane function
A cell with a damaged membrane dies from
disruption in metabolism or lysis.
These drugs have specificity for a particular
microbial group, based on differences in types
of lipids in their cell membranes.
_____________ interact with phospholipids
and cause leakage, particularly in gramnegative bacteria
Amphotericin B and nystatin form complexes
with sterols on fungal membranes which
causes leakage.
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4. Drugs that disrupt cell membrane function
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3. Drugs that inhibit nucleic acid synthesis
may block synthesis of nucleotides, inhibit replication,
or stop transcription
_____________ inhibition – drug competes with
normal substrate for enzyme’s active site
_____________ effect – an additive effect, achieved
by multiple drugs working together, requiring a lower
dose of each
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2. Drugs that inhibit nucleic acid synthesis
(and also 4. drugs that block metabolism)
_____________(ciprofloxacin) blocks gyrase
_____________ blocks RNA pol (transcription)
• Sulfonamides and _______________________________
(synergistic) -- block enzymes required for
tetrahydrofolate (THFA) synthesis
• THFA is needed for DNA & RNA
synthesis. (coenzyme)
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Figure 12.6 (a)
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Competitive inhibition of PABA by sulfa drug
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4. Drugs that block protein synthesis
Ribosomes of eucaryotes differ in size and
structure from procaryotes, so antimicrobics
usually have a selective action against
procaryotes. But they can also damage the
eucaryotic _____________ .
Abt can block mRNA, peptide bonds, tRNA
binding, etc.
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Survey of major antimicrobial drug
groups
Antibacterial drugs
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Antibiotics
Synthetic drugs
Antifungal drugs
Antiparasitic drugs
Antiviral drugs
About 260 different antimicrobial drugs are
classified in 20 drug families.
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Antibacterial antibiotics
Penicillins
Cephalosporins
Other beta-lactam antibiotics
Aminoglycosides
Tetracycline antibiotics
Chloramphenicol
Other Streptomyces antibiotics
The Bacillus antibiotics
New classes
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Penicillins
Cell wall inhibitors.
Source: Penicillium
Examples: “-cillin” such as penicillin,
ampicillin, amoxicillin, methicillin etc.
MOA: blocks PGN synthesis (CW)
Application: Gram positive, some Gram neg.
Structure: B-lactam, thiaxolidine, varying side
chains
Problems: allergy, bleeding, diarrhea (host);
resistance in bacteria (via lactamase,
penicillinase)
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Penicillins
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Cell wall inhibitors.
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Cephalosporins
Cell wall inhibitors.
Source: Cephalosporium
Examples: Ceph- cef- kef- drugs (ex.
Cephalexin)
MOA: blocks CW synthesis
Application: depends on “generation”
Structure: B-lactam, ring, varying side
chains (2)
Problems: less allergies, but some need
parenteral administration, can affect WBC
4 generations exist: each group more effective against gram-negatives than
the one before with improved dosing schedule and fewer side effects
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Cephalosporins - generations
Gram+ cocci, some
Gram-
More G- than 1st gen
(Enterobacter, Proteus,
Haemophilus)
Broad spectrum against
enteric bacteria with
beta-lactamases
Ex. Cephalexin (Keflex)
cefepime – widest
range; both gramnegative and grampositive
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Cell wall inhibitors.
Other beta-lactam antibiotics
Imipenem – broad-spectrum drug for infections
with aerobic and anaerobic pathogens; low
dose, oral, few side effects
Aztreonam –isolated from bacteria
Chromobacterium violaceum – newer narrowspectrum drug for infections by gram-negative
aerobic bacilli. May be used by people allergic to
penicillin- it is a monobactam. Given IV.
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Disrupt cell wall synth.
MOA of B-lactam antibiotics
PGN (made of NAM and NAG) are crosslinked by the enzyme transpeptidase
This is the final step in CW syntheis
B-lactam abt inhibit transpeptidase – they
mimic the normal substrate and bind to the
active site.
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Cell wall inhibitors.
Non Beta-lactam Cell Wall Inhibitors
_____________–narrow-spectrum, effective
against penicillin & methicillin resistant
staphylococcal infections; very toxic, hard to
administer, restricted use – inhibits CW synthesis
(NAM/NAG polymerization)
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MOA: Blocks CW synthesis; produced by a strain of
Bacillus subtilis; Application: narrow-spectrum, major
ingredient of neosporin ointment (topical)
Isoniazid –works by interfering with mycolic acid
synthesis; used with rifampin to treat TB; blocks FA
reductase (metabolism) (Nydrazid ®)
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2. Antibiotics That Damage Bacterial
Cell Membranes
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MOA: peptide with fatty acid component,
detergent activity
Application: narrow-spectrum; drug resistant
Pseudomonas aeruginosa & UTI
Problems: limited by toxicity to kidney;
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3. Drugs that Act on DNA or RNA
Fluoroquinolones – work by binding to DNA
gyrase and topoisomerase IV
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Broad spectrum effectiveness
Concerns have arisen regarding the overuse of
quinoline drugs
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CDC is recommending careful monitoring of their
use to prevent ciprofloxacin-resistant bacteria
norfloxacin, _____________ – UTI, STD, GI,
osteomyletitis, respiratory & soft tissue infections
sparofloxacin, levofloxacin – pneumonia,
bronchitis, sinusitis
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3. Drugs that Act on DNA or RNA
_____________– limited spectrum, cannot
pass through many cell membranes, used
to treat gram-positive bacteria, TB, leprosy
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Blocks TRANSCRIPTION
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4. Drugs That Interfere with Protein Synthesis
Aminoglycosides
Products of various species of soil actinomycetes in
genera Streptomyces and Micromonospora
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aminoglycosides
Source: Actinomycetes (like Streptomyces)
Examples: streptomycin, gentamicin,
amikacin, neomycin
MOA: blocks translation (inhibits initation,
binds 30S ribosomal subunit)
Application: relatively broad (aerobic G-, TB)
Structure: 6C ring with 2 amino sugars
Problems: diarrhea, kidney, EAR problems
Sometimes combined with Amp to treat systemic G+ infections - endocarditis
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4. Drugs That Interfere with Protein Synthesis
Aminoglycosides – Broadspectrum, inhibit protein
synthesis, especially useful
against aerobic gramnegative rods and certain
gram-positive bacteria
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_____________– bubonic
plague, tularemia, TB
Gentamicin – less toxic, used
against gram-negative rods
Newer – tobramycin and
amikacin gram-negative
bacteria
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Other antibiotics produced by Streptomyces:
A. __________
MOA: block protein synthesis (30S)
Application: Broad-spectrum, Doxycycline &
minocycline – oral drugs taken for STDs,
Rocky Mountain spotted fever, Lyme
disease, typhus, acne & protozoa
Problems: kills GI flora, can discolor teeth in
children, causes photosensitization
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B. _____________
Source: Streptomyces venezuelae– is totally
synthetic now
MOA: Blocks peptide bond formation
Application: Potent broad-spectrum drug with
unique. Typhoid fever, brain abscesses,
rickettsial & chlamydial infections
Structure: nitrobenzene
Problems: **Very toxic, restricted uses, can
cause irreversible damage to bone marrow
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C. _____________ and other macrolide
antibiotics
MOA: Attaches to ribosome (50S)
Application:
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Broad-spectrum, fairly low toxicity.
Taken orally for Mycoplasma pneumonia, legionellosis,
Chlamydia, pertussis, diphtheria and as a prophylactic
prior to intestinal surgery (also strep throat, ear
infection)
For penicillin-resistant – gonococci, syphilis, acne
Newer semi-synthetic macrolides – clarithomycin,
azithromycin (Z-pak®)
Structure: macrolide, large lactone ring with
sugars
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Macrolide antibiotics
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5. Drugs That Block Metabolic
Pathways
Most are synthetic; most important are ____________
or sulfa drugs - first antimicrobic drugs
Narrow-spectrum; block the synthesis of folic acid by
bacteria (and indirectly DNA synthesis)
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Sulfisoxazole – shigellosis, UTI, protozoan infections
Silver sulfadiazine – burns, eye infections
_____________ – given in combination with
sulfamethoxazole – UTI, PCP
Sulfonamides and trimethoprim block THFA synthesis
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Structure of sulfonamides
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New classes of antibiotics
Formulated from pre-existing drug classes
Three new drug types:
1. Fosfomycin trimethamine – a phosphoric acid;
effective as alternate treatment for UTIs, inhibits cell
wall synthesis
2. _____________– effective against Staphylococcus &
Enterococcus that cause endocarditis & surgical
infections; inhibits protein synthesis (binds 50S)
3. Daptomycin – directed mainly against gram-positive;
disrupts membrane function
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Newly Developed Classes of Antimicrobials
Ketolides – telitromycin (Ketek), new drug with
different ring structure from Erythromycin; used
for infection when resistant to macrolides
_____________– linezolid (Zyvox®); synthetic
antimicrobial that blocks the interaction of mRNA
and ribosome
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Used to treat _______________________
_______________________________________
_________________________________________
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Antifungal agents
Problem: _________________________
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drug groups:
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Macrolide polyene antibiotics
Griseofulvin
Synthetic azoles
flucytosine
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Macrolide polyene
MOA: bind fungal membranes, increase
permeability (fungal membranes have sterols)
Examples:
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Amphotericin B – mimic lipids, most versatile &
effective, topical & systemic treatments
Nystatin – topical treatment
Structure: steroid
Applications:
Candida, ringworm,
histoplasmosis, cryptococcus
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Other antifungals
Griseofulvin
Application: stubborn cases of dermatophyte
infections, nephrotoxic
Synthetic azoles – Application: broad-spectrum;
Examples: ketoconazole, clotrimazole,
miconazole; Structure: complex ring structure
Flucytosine – MOA/Structure: analog of
cytosine; Application: cutaneous mycoses or in
combination with amphotericin B for systemic
mycoses
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Antifungal drugs
Azoles
Flucocytozine
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Antiparasitic Chemotherapy
1. Antiprotozoan drugs
Antimalarial drugs –
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quinine, chloroquinine, primaquine, mefloquine –
used as prophyllaxis or treatment
Anti -amoeba, -flagellates, -ciliates–
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Used for infections with Entamoeba, Giardia,
Trichomonas
metronidazole (Flagyl), quinicrine, sulfonamides,
tetracyclines
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Antiparasitic chemotherapy
2. Antihelminthic drugs – immobilize,
disintegrate, or inhibit metabolism
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Niclosamide – destroys scolex
Praziquantel – tapeworms, trematodes
Mebendazole, thiabendazole – broad-spectrum –
inhibit function of microtubules, interferes with
glucose utilization and disables them
Pyrantel, piperazine – paralyze muscles
Ivermectin – works on neurotransmitters and
paralyzes worm or insect
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Antiviral drugs – 3 MOA
Block _____________ into host cell
Fuzeon – blocks HIV by preventing interaction of receptors
Amantidine – blocks influenza entry and release (blocks fusion and
uncoating)
Tamiflu - blocks influenza neuraminidase (needed for entry)
Block _______________________________
Acyclovir – herpesviruses – binds viral DNApol (Zovirax) Purine
analog. Also Valacyclovir (Valtrex)
AZT (zidovudine) – thymine analog – HIV – RT inhibitor so viral
genome can’t be replicated
Nevirapine - blocks enzyme - RT binding site  no RNA DNA
Prevent ___________ of viral particles and release
Protease inhibitors (Saquinavir, Ritonavir)– HIV – inactivate
enzyme so viral proteins are not functional
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Interferon
IFN is a human cytokine, naturally produced by
cells (leukocytes) as part of the immune response
It is the ___________________________ in your
body! (also anticancer)
recIFN can be used therapeutically:
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Shorten herpes healing time
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Reducing colds and warts
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Slowing cancer progress; treating rare cancers
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Treating HepC, papillomavirus, Kaposi’s sarcoma
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Four Mechanisms drug resistance
1. Drug _______________ – penicillinases
2. Decreased _______________ to drug or
increased elimination of drug from cell
3. Change in _______________ patterns
4. Change in drug ________________
Drug resistance can be carried as R factors
(plasmids carrying resistance genes)
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Mechanisms drug resistance
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Selection for drug resistance
Go to this link:
http://www.sumanasinc.com/scienceinfocus/antibiotics/antibiotics_fla.html
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Human behavior that leads to drug
resistance
Doctors over-prescribing antibiotics
asking for antibiotics when they are not
needed (viral infections)
failing to finish an antibiotic prescription
saving the unused medication and taking it
later for another illness
taking antibiotics before symptoms arise
simply to avoid getting sick
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Other factors that lead to microbial drug resistance
Hospital setting – Lots of Abt being used,
weakened (sick and easy to infect) hosts
Resistance in ______________ on antibiotic
regimens (these microbes are also in the meats
we eat)
Resistance spreads rapidly both geographically
(exporting foods) and within populations
(transformation, conjugation, etc.)
Viruses – have rapid ___________ rate (HIV)
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Side effects of drugs
1. Toxicity to organs – liver (detox), kidney
(excretion; sulfonamides), GI (kills flora),
bone marrow (anemia, chloramphenicol),
nervous system (aminoglycosides),
Teeth/bones (tetracycline)
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2. Allergic
responses – true
penicillin allergy is
to benzlpenicilloyl
(product of
metabolism of Pen)
3. Suppression and
alteration of
microflora
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