Discovery of antimicrobial drugs › Paul Erlich (1909)found the first pharmaceutical effective for...
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Transcript of Discovery of antimicrobial drugs › Paul Erlich (1909)found the first pharmaceutical effective for...
Discovery of antimicrobial drugs› Paul Erlich (1909)found the first
pharmaceutical effective for treatment of syphilis: Salvarsan Arsphenamine highly toxic
› Sulfonamide was the first sulfa drug In vitro derivative of Prontosil dye effective against streptococcal infections Bayer Labs, 1939 Nobel prize in Medicine
Discovery of antibiotics› Penicillin discovered by Alexander Fleming
Identified mold Penicillium that produced a bactericidal substance that was effective against a wide range of gram + microbes
Inhibits cell wall synthesis Mass production of penicillin during WWII
› Streptomycin (1943) isolated from soil bacterium Streptomyces griseus by Selman Waksman Bacteriostatic Inhibits protein synthesis by binding to ribosome
Development of new generation of drugs› In 1960s scientists
alteration of drug structure gave them new properties Penicillin G altered to
create ampicillin Broadened spectrum
of antimicrobial killing
Most modern antibiotics come from organisms living in the soil› Includes bacterial species Streptomyces and
Bacillus as well as fungi Penicillium and Cephalosporium
To commercially produce antibiotics› Strain is grown until maximum antibiotic
concentration is reached› Drug is extracted from broth medium› Extensively purified› May be chemically altered
Termed semi-synthetic
Selective toxicity› Antibiotics cause greater harm to
microorganisms than to human host› Toxicity of drug is expressed as therapeutic
index Lowest dose toxic to patient divided by dose
typically used for treatment High therapeutic index = less toxic to patient Narrow therapeutic index = more toxic, monitor
closely
Antimicrobial action› Bacteriostatic drugs
Inhibit bacterial growth rely on host immunity
› Bacteriocidal drugs Kill bacteria Most useful in situations when host defenses
cannot control pathogen
Spectrum of activity› Antimicrobials vary with respect to range
of organisms controlled Narrow spectrum
Work on narrow range of organisms Gram-positive only OR Gram-negative only
Advantage: effects pathogen only Disadvantage: requires identification of pathogen
Broad spectrum Advantage: Work on broad range of organisms Disadvantage : disruption of normal flora
Effects of combinations of antimicrobial drugs› Combination sometimes used to treat
infections Synergistic: whole is > sum Antagonistic: whole is < sum Additive: whole is the sum
Tissue distribution, metabolism and excretion› Drugs differ in how they are distributed,
metabolized and excreted› Half-life: Rate of elimination of drug from
body Time it takes for the body to eliminate one
half the original dose in serum Half-life dictates frequency of dosage
› Patients with liver or kidney damage tend to excrete drugs more slowly
Adverse effects› Allergic reactions› Toxic effects› Suppression of normal flora› Antimicrobial resistance
Mechanism of action include:› Inhibition of cell wall synthesis
Penicillins, Cephalosporins, Vancomycin, Bacitracin
› Inhibition of protein synthesis Aminoglycosides, tetracyclines, macrolides, chloramphenicol,
lincosamides
› Inhibition of nucleic acid synthesis Fluoroquinolones, rifamycins
› Inhibition of metabolic pathways Sulfonamides, trimethoprim
› Interference with cell membrane integrity Polymyxin
Inhibition of cell wall synthesis› Antimicrobials that interfere
with the synthesis of peptidoglycan
› These drugs have very high therapeutic index
› Antimicrobials of this class include β lactam drugs (penicillin,
cephalosporin) Vancomycin Bacitracin
Drugs vary in spectrum Some more active against Gram (+) Some more active against Gram (-)
› Resistance through production of β-lactamase enzyme
› Penicillins + β lactamase inhibitor Augmentin = amoxicillin + clavulanic
acid
Vancomycin› Inhibits formation of glycan
chains Does not cross lipid
membrane of Gram (-)› Important in treating
infections caused by penicillin resistant Gram (+) organisms
› Given intravenously due to poor GI absorption
› Acquired resistance most often due to alterations in side chain of NAM molecule Prevents binding of
vancomycin to NAM component of glycan
Bacitracin› Interferes with transport of PTG precursors
across cytoplasmic membrane› Toxicity limits use to topical applications› Common ingredient in non-prescription
first-aid ointments
Inhibition of protein synthesis› Structure of prokaryotic ribosome acts as
target for many antimicrobials of this class› Drugs of this class include
Aminoglycosides Tetracyclins Macrolids Chloramphenicol Lincosamides Oxazolidinones Streptogramins
Aminoglycosides› Irreversibly binds to 30S
ribosomal subunit Blocks initiation
translation Causes misreading of
mRNA› Not effective against
anaerobes, enterococci and streptococci
› Often used in synergistic combination with β-lactam drugs
› Examples include Gentamicin, streptomycin
and tobramycin › Side effects with
extended use include Nephrotoxicity Otto toxicity
Tetracyclins› Reversibly bind 30S
ribosomal subunit Blocks attachment of
tRNA to ribosome Prevents continuation of
protein synthesis
› Narrow range: Effective against certain Gram (+) and Gram (-)
Macrolids› Reversibly binds to 50S
ribosome Prevents continuation of
protein synthesis› Effective against variety
of Gram (+) organisms› Often drug of choice for
patients allergic to penicillin
› Macrolids include Erythromycin,
clarithromycin and azithromycin
› Resistance can occur via modification of RNA target
Chloramphenicol› Binds to 50S
ribosomal subunit Prevents peptide bond
formation
› Wide spectrum› Drug of last resort› Rare but lethal side
effect is aplastic anemia
Lincosamides: clindamycin› Binds to 50S ribosomal subunit
Prevents continuation of protein synthesis› Inhibits variety of Gram (+) and Gram (-)
organisms Useful in treating infections from intestinal
perforation Especially effective against Bacterioides fragilis and
Clostridium difficile
New class effective against β-lactams and vancomycin resistant Gram (+) forms› Oxazolidinones
Binds 50S ribosomal subunit Interferes with initiation
› Streptogramins Bonds to two different sites on 50S
ribosomal subunit
Fluoroquinolones› Inhibit action of topoisomerase DNA gyrase
Topoisomerase maintains supercoiling of DNA
› Broad-Spectrum: Effective against Gram (+) and Gram (-)
› Examples include Ciprofloxacin and ofloxacin
› Resistance due to alteration of DNA gyrase
Rifamycins› Block prokaryotic RNA polymerase
initiation of transcription
› Rifampin most widely used rifamycins› Broad-spectrum: Effective against many Gram
(+) and some Gram (-) as well as Mycobacterium
› Treatment of › Tuberculosis › Hansen’s disease › N. meningitidis meningitis
› Resistance develops rapidly
Folate inhibitors Mode of actions to
inhibit the production of folic acid
Mimic PABA
› Antimicrobials in this class include Sulfonamides Trimethoprim
› Human cells lack specific enzyme in folic acid pathway
› Resistance due to plasmid
› Polymixn B most common
Common ingredient in first-aid skin ointments
› Binds membrane of Gram (-) cells Alters permeability Also binds eukaryotic
cells Limits use to topical
application
Susceptibility of organism to specific antimicrobials is unpredictable
Often drug after drug tried until favorable response was observed
Better approach› Determine susceptibility› Prescribe drug that acts against offending
organism Best to choose one that affects as few others as
possible
MIC = Minimum Inhibitory Concentration
Quantitative test to determine lowest concentration of specific antimicrobial drug needed to prevent growth of specific organism
Kirby-Bauer disc diffusion method› qualitative
determination of susceptibility
› Discs impregnated with specific concentration of antibiotic placed on plate and incubated
› Clear zone of inhibition around disc reflects susceptibility
size of clearing zone indicates if susceptible or resistant
E-test› Uses strips
impregnated with gradient concentration of antibiotic
› Test organism will grow and form zone of inhibition Zone is tear-drop
shaped Zone will intersect
strip at inhibitory concentration
Mechanisms of resistance› Drug inactivating enzymes
Penicillinase breaks β-lactam ring of penicillin antibiotics
› Alteration of target molecule Minor structural changes in
antibiotic target can prevent binding Changes in ribosomal RNA
prevent macrolids from binding to ribosomal subunits
Mechanisms of resistance› Decreased uptake of the
drug Alterations in porin proteins
decrease permeability of cells
› Increased elimination of the drug Some organisms produce
efflux pumps Tetracycline resistance
Acquisition of resistance› Can be due to spontaneous mutation
vertical evolution
› Or acquisition of new genes horizontal transfer Plasmid mediated
Spontaneous mutation› Example of spontaneous mutation
Resistance to streptomycin is result a change in single base pair encoding protein to which antibiotic binds
› When antimicrobial has several different targets it is more difficult for organism to achieve resistance through spontaneous mutation
Acquisition of new genes through gene transfer› Most common mechanism of transfer is
through conjugation Transfer of R plasmid Plasmid often carries several different
resistance genes Organism acquires resistance to several different
drugs simultaneously
Examples of emerging antimicrobial resistance› Enterococci
Intrinsically resistant to many common antimicrobials
Some strains resistant to vancomycin VRE: Vancomycin resistant enterococcus
Many strains achieve resistance via transfer of plasmid
Staphylococcus aureus› Common cause of nosocomial infections› Becoming increasingly resistant
Most strains acquired resistance to penicillin Until recently most infections could be treated
with methicillin MRSA methicillin resistant Staphylococcus aureus
many of these strains still susceptible to vancomycin VISA vancomycin intermediate Staphylococcus aureus
Streptococcus pneumoniae› Has remained sensitive to
penicillin Some strains have now gained
resistance Resistance due to modification in
genes coding for penicillin-binding proteins
Acquisition via DNA mediated transformation
Slowing emergence and spread of resistance› Responsibilities of physicians and healthcare
workers Prescribe antibiotics for specific organisms Educate patients on proper use of antibiotics
› Responsibilities of patients Follow instructions carefully Complete prescribed course of treatment
Misuse leads to resistance
Slowing emergence and spread of resistance› Importance of an educated public
Greater effort made to educate public about appropriateness and limitations of antibiotics Antibiotics have no effect on viral infections Misuse selects antibiotic resistance in normal flora
› Global impacts of the use of antimicrobial drugs Organisms which develop resistance in one country can
be transported globally Many antimicrobials are available as non-prescription
basis Use of antimicrobial drugs added to animal feed
Produce larger more economically productive animals Also selects for antimicrobial resistant organisms
Available antiviral drugs effective specific type of virus› None eliminate latent virus
Targets include› Viral uncoating› Nucleoside analogs› Non-nucleoside polymerase
inhibitors› Non-nucleoside reverse
transcriptase inhibitors› Protease inhibitors› Neuraminidase inhibitors
Viral uncoating› Drugs include amantadine and rimantadine› Mode of action is blocking uncoating of
influenza virus after it enters cell Prevents severity and duration of disease
› Resistance develops frequently and may limit effectiveness of drug
Nucleoside analogs› Incorporation of analog results in termination
of growing nucleotide chain› Examples of nucleoside analogs
Zidovudine (AZT) Didanosine (ddI) Lamivudine (3TC)
Non-nucleoside polymerase inhibitor› Inhibit activation of viral polymerases by
binding to site other than nucleotide binding site Example = foscarnet and acyclovir
Non-nucleoside reverse transcriptase inhibitor› Inhibits activity of reverse transcriptase by
binding to site other than nucleotide binding site Example = nevirapine, delavirdine, efavirenz
Used in combination to treat HIV
Protease inhibitor› Inhibit HIV encoded enzyme protease
Enzyme essential for production of viral particles
Examples = indinavir and ritonavir Neuraminidase inhibitor
› Inhibit neuraminidase enzyme of influenza Enzyme essential for release of virus Examples = zanamivir and oseltamivir
Target for most antifungal medications is plasma membrane› Ergosterol
Include› Polyenes› Azoles› Allylamines
Other targets› Cell wall synthesis› Cell division› Nucleic acid synthesis
Cell wall synthesis› Echinocandins
interfere with synthesis of fungal cell wall Cell division
› Griseofulvin Exact mechanism unknown
Appears to interfere with action of tubulin Selective toxicity may be due to increased uptake by fungal
cells Used to treat skin and nail infections
Nucleic acid synthesis› Flucytosine
Inhibits enzymes required for nucleic acid synthesis Flucytosine converted to 5-fluorouricil
Many antiparasitic drugs most likely interfere with biosynthetic pathways of protozoan parasites or neuromuscular function of worms
Example of parasitic drugs includes› Malarone
Synergistic combination of atovaquone and proguanil HCl
Interferes with mitochondrial electron transport and disruption of folate synthesis