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85 Cards in this Set
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Antimicrobial Chemotherapeutic Agents:
1. Desirable properties of antimicrobial agents What makes a good antimicrobial chemotherapeutic agent? |
Selective toxicity
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Selective toxicity
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kills microbes, but minimal damage to host
Measurement of selective toxicity: • Minimum effective dose for 50% of the population = ED50 • Lethal dose of a drug for 50% of the population = LD50 |
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Therapeutic index
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LD50 / ED50
Can go from 2 to 100 • The index better the chemotherapeutic higher the index, the agent As few side effects as possible – undesirable consequences to the host |
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Common bacterial cell targets of antibiotics:
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Common bacterial cell targets of antibiotics:
• Biochemical pathways unique to certain pathogens • Prokaryotic transcription or translation (ribosomes) • Peptidoglycan synthesis • Prokaryotic cell membrane permeability |
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Paul Ehrlich
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originally discovered in 1896 but forgotten;
rediscovered in 1929 by Alexander Fleming, who found that Penicillium produced the substance; 1939 – penicillin finally purified by two Oxford scientists • Streptomycin: 1944; chloramphenicol, neomycin, terramycin, tetracycline: 1953 |
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Chemotherapeutic agents
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chemical compounds that can be used internally for control of infectious diseases
-synthetic agents and antibiotics |
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synthetic agents
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synthetic growth factor analogs that
inhibits a necessary step in a microbial metabolic pathway y p p |
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antibiotics
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natural chemical compound products that
inhibit or kill microorganisms |
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Narrow spectrum antibiotics
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inhibit or kill only select bacteria
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Broad spectrum antibiotics
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effective against a wider range of bacteria
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Antibiotics: Inhibitors of important microbial cellular processes
modes of action |
A. Inhibition of a critical pathway
B. Inhibition of DNA/RNA synthesis C. Inhibition of cell wall synthesis D. Inhibition of protein synthesis E. Alteration of cell membranes |
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Growth factor analog
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synthetic compound that is structurally similar
to a growth factor but slight differences make it not work in the cell |
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Analogs are known for many important biomolecules:
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(vitamins, amino
acids, purines, and pyrimidines) |
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Sulfa Drugs
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inhibitors of folic acid biosynthesis
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Sulfanilamide is an analog of:
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an analog of p-aminobenzoic acid
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Mode of action of sulfanilamide:
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Inhibits the
incorporation of p- aminobenzoic acid into the vitamin folic acid → bacteria are no longer able to make folic acid |
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Bacteria synthesize their own
folic acid – most animals get folic acid only from their ___ |
diet
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Sulfa drugs are selective
agents against ____. |
bacteria
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____ is a lipid that complexes with
peptidoglycan in the cell wall of Mycobacteria |
Mycolic acid
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Isoniazid
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an analog of nicotinamide, a
precursor of mycolic acid most effective single drug for the treatment of tuberculosis ex. narrow spectrum antibiotic |
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Bacterial DNA gyrase supercoiling
is responsible for |
DNA to help packaging in the bacterial cell
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Fluoroquinolone drugs interfere with
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DNA gyrase
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Because DNA gyrase is found in Gram-negative and gy g
Gram-positive bacteria, ______can be used to treat both types of infections |
Fluoroquinolones
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Ciprofloxacin (= Cipro) is used to treat:
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urinary
infections and anthrax |
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____ are antimicrobial agents produced by microbes
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Antibiotics
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function of antibiotics
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Function:
microbial chemical warfare. Microbes in the same environment compete for the same nutrients. They gain a strong advantage by inhibiting or killing other species |
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The ____ antibiotics inhibit cell wall synthesis
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β-lactam
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β-lactam antibiotics get their name from their____.
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β-lactam ring
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first β-lactam antibiotic
discovered and produced commercially |
Penicillin G
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Penicillin G is Effective mainly against:
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Gram+ organisms
(Gram- are impermeable to penicillin G) |
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Penicillin G mode of action:
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prevent transpeptidase
reaction the enzyme = inhibit β-ring by binding to peptidoglycan synthesis |
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Transpeptidases are also known as
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penicillin-binding proteins
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Penicillin-transpeptidase complex
stimulates |
release of autolysins by bacteria.
Autolysins degrade the existing cell wall |
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Bacteria that produce the enzyme β-lactamase
are resistant to |
penicillin
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Some penicillin semisynthetic derivatives are
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resistant to β-lactamase
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Cephalosporins
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also β-lactam antibiotics
and act in the same way as penicillins more resistant to β-lactam |
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Vancomycin
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not a β-lactam antibiotic,
peptidoglycan but binds to precursors to prevent cell wall synthesis. Used to treat penicillin-resistant bacteria |
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Aminoglycosides:
Bind to the: |
Made of amino sugars linked by
glycosidic bonds Bind to the 30S subunit of the ribosome |
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Mode of bacterial resistance for Aminoglycosides:
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modification of the drug
by an “N-acetyltransferase” enzyme → inactive form |
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Because of serious side-effects and bacterial resistance, aminoglycosides are only used as:
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reserve antibiotics when others fail
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Tetracyclines in hibit:
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Inhibit almost all Gram- and Gram+
bacteria |
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Tetracyclines bind to the:
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Bind to the 30S subunit of the ribosome
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Many different tetracyclines are produced _____.
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semisynthetically
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Have been widely used in the past an nutritional
supplements for swine and poultry |
Tetracyclines
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Tetracyclines are Produced by ____ species
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Streptomyces
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Macrolides:
They bind to: |
Contain lactone rings linked to sugars
Bind to the 50S subunit of the ribosome |
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Macrolides are Best known is
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erythromycin
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Macrolides target a broad spectrum of:
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Target a broad spectrum of bacteria
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Macrolides are commonly used:
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Commonly used for patients allergic to penicillins
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Marcrolides are produced by:
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Produced by Streptomyces species
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Daptomycin
Example: |
A cyclic lipopeptide natural product
from certain Streptomyces species “ionophore” antibiotic |
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Daptomycin binds to:
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Binds to bacterial cytoplasmic membranes, forms
pores, resulting in depolarization of the membrane → death no energy → cell |
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Daptomycin has rare instances of:
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Rare instances of resistance
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Monensin
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an ionophore used in animal feed
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Platensimycin
produced by: |
Inhibits enzyme involved in fatty acid
(and membrane) biosynthesis; produced by Streptomyces platensis |
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Plantensimycin is effective against:
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Effective against many Gram+ bacteria, including
methicillin and vancomycin-resistant species |
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Plantensimycin has no know potential for development of:
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resistance
by pathogens |
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Acquired antibiotic drug resistance
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acquired ability of a microbe to resist the effect of a drug to which it is initially susceptible
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Methods of antibiotic resistance used by bacteria:
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1 A particular taget (binding site or enzyme) may be lacking in the organism
2. Organisms may be impermeable to the drug 3. Modification of the antibiotic to an inactive form 4. Target of the antibiotic may be altered 5. Mutation that results in a metabolic bypass around a step blocked by an antibiotic 6. The organism can pump the antibiotic out of the bacterium with an efflux pump |
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Role of plasmids in microbial antibiotic resistance:
Plasmids encode antibiotic resistance enzymes and proteins = _____. R plasmids originated before clinical use of many antibiotics |
“R” (resistance)
plasmids. |
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Why are antibiotic resistant strains of pathogenic organisms more prevalent today?
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Use of antibiotics creates great selective pressure favoring microbes that are
resistant to the drug and selecting against microbes that are sensitive to the drug • Overuse of antibiotics results in increased prevalence of drug-resistant strains p g within human populations • Antibiotics are also used as additives in agricultural settings for animal feeds, fish farming, and even fruit production |
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Inclusion of fluoroquinolone (FQ) in
animal feed can lead to increased prevalence of ____ in humans |
FQ-resistant
Campylobacter |
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clinical trial system
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for new drug approval the clinical trial system by Food and Drug
Administration (antimicrobials and all other drugs must go through this process) |
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clinical trial system process:
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drug discovery
phase I trials phase II trials phase III trials FDA approval post marketing/phase VI discovery to maket: 20-25 years |
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toxicity
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Most antiviral drugs also affect the host cell
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Reverse transcriptase inhibitors: Most successful agents against the _____
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AIDS virus
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Nucleoside reverse transcriptase inhibitors
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Useful against retroviruses (viruses with
RNA genome); block the RNA → DNA step catalyzed by reverse transcriptase; get incorporated into the newly formed DNA and block the next step |
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Non-nucleoside reverse transcriptase inhibitors
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Bind directly to the reverse transcriptase to block the RNA → DNA step
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Protease inhibitors:
Effective for the treatment of: |
Prevent cleavage of
important proteins required for viral replication • Effective for the treatment of HIV, bind to the HIV protease |
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Fusion inhibitors
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prevent entry of the
into the virus cell • Enfuvirtide, binds to the HIV gp41 membrane protein |
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Neuraminidase inhibitors
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prevent virus
release from infected cells [Tamiflu, Relenza] for influenza only |
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Recent therapies for HIV treatment
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Recent therapies for HIV treatment:
Multi-drug combinations – use of 2-3 different drugs at once has a more beneficial Combivir® = Lamivudine + Zidovudine ( = effect than each drug alone e.g., AZT + protease inhibitors 3TC + AZT) Combined antiviral drugs improve efficiency of AZT therapy |
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Because fungi are ____, they share a lot of their cellular machinery
with with animals and humans → many antifungal drugs have toxic side- |
eukaryotes
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a few drugs target unique fungal structures or metabolic processes =
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they are selectively toxic for fungi only
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Ergosterol inhibitors:
Ergosterol: |
sterol present the cytoplasmic in membrane of fungi, instead of cholesterol
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Two types of ergosterol inhibitors
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1. Bind to ergosterol; cause membrane
permeability and cell death 2. Inhibit ergosterol biosynthesis |
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Inhibitors of cell wall synthesis
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1,3 β-D glucan synthase forms glucan polymers in fungal cell walls; animal
cells do not have cell walls or 1,3 β-D glucan synthase β f • Echinocandins inhibit 1,3 β-D glucan synthase, resulting in fungal cell death • Polyoxins: inhibitors of chitin biosynthesis (used as agricultural fungicides) |
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Echinocandins inhibit:
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1,3 β-D glucan synthase, resulting in fungal cell death
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Polyoxins
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inhibitors of chitin biosynthesis (used as agricultural fungicides)
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desirable properties of antimicrobial agents
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as few of side effects as possible
selective toxicity |
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inhibitors of folic acid
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sulfa drugs
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cell wall inhibitor (example)
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mycolic acid
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inhibitors of DNA packaging
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Fluoroquinolone
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antibiotics that inhibit protein synthesis
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Aminoglycosides
Tetracyclines Macrolides |
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antibiotics interfering with cell membrane properties
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Daptomycin
Platensimycin |