Antimicrobial Agents Use when balance tips in favor of invading
MO Slide 2 Antimicrobial Therapy When balance between MO and host
tilts in direction of MO, bodys normal defense cannot prevent or
overcome disease Turn to Chemotherapy - treatment of disease with
chemical drugs into body Slide 3 Chemotherapeutic Agents
Antimicrobial - to treat infectious disease, act within host
Antibiotic - produced naturally by MO (bacteria, fungi) Synthetic
drug synthesized, made in laboratory Slide 4 Slide 5 Successful
Antimicrobial Selective toxicity - harm MO not host (all drugs have
some side-effects) No hypersensitivity reaction does not elicit
harmful host immune reaction Penetrate - gets to site of tissue
infection rapidly, retain for adequate time No resistance - MO not
readily able to counteract it Slide 6 Activity of Antimicrobial E
asier to find against prokaryote as different from eukaryotic cell
Fungi, protozoan, helminth are eukaryotes; make finding drug with
selective toxicity more difficult Especially difficult to find drug
against virus, require host cell to replicate Slide 7 Spectrum of
Antibiotics Narrow spectrum - affects relatively few kinds of
bacteria Broad spectrum - effective against large number Gram(+)
& Gram(-) bacteria Problem of broad spectrum antibiotic use is
NF destroyed, allow certain NF to flourish and cause opportunistic
infection Superinfection - overgrowth of NF due to antibiotic
treatment for an initial infection Slide 8 Action of Antimicrobial
Bacteriocidal - kill bacteria Bacteriostatic - prevent growth of
bacteria; hosts defense of phagocytosis and antibody eliminate
bacteria Different areas in bacteria serve as target for action of
antimicrobial: Cell wall Ribosome Plasma membrane DNA, RNA
Metabolite Slide 9 Bacterial Cell Wall Cross Linking Interference
with synthesis of bacterial cell wall should not harm host
Bacterial cell wall contain peptidoglycan not found in eukaryotic
cell Many antibiotics prevent synthesis of peptidoglycan by
interfering with linkage by peptide cross-bridge Slide 10
Inhibition of Bacteria Cell Wall Biosynthesis: Lactam Ring These
antibiotics contain beta lactam ring that bind to group of
bacterial enzymes called penicillin binding proteins (PBP) PBP
involved in peptidoglycan cell wall synthesis Binding of PBP
prevents peptide cross linking, cell wall weakened, bacteria
undergoes lysis Slide 11 Beta Lactam Ring Antibiotics Affect cell
wall synthesis, only effective on actively growing MO These
antibiotics include: Penicillin and derivatives (ampicillin,
methacillin, oxacillin, amoxacillin, augmentin) Cephalosporin
(cephalothin, cefuroxime, ceftazidime, cefoxitin) Carbapenem
(imipenem) Monobactam (aztrenam) Slide 12 Inhibition of Bacterial
Cell Wall Biosynthesis: Others Bacitracin - interferes with
synthesis of peptidoglycan by inhibiting recycling of metabolites
Vancomycin - binds to precursors used in cell wall synthesis;
interfere with enzymes that incorporate these precursors into
growing cell wall Slide 13 Inhibition of mRNA Translation P rotein
synthesis common feature of all cells Ribosome structure of
eukaryote and prokaryote cell differ (80S vs 70S) Many
antimicrobials specifically interfere with mRNA protein synthesis
on prokaryotic 70S ribosomes Some antimicrobials act on 50S subunit
of the ribosome, while others act on 30S subunit of ribosome Slide
14 Inhibition of Bacteria Translation Chloramphenicol - acts at
50S, inhibit formation of peptide bond Erythromycin - acts at 50S,
prevent translocation movement of ribosome Tetracycline - acts at
30S, interfere with tRNA attachment Aminoglycosides (gentamycin,
streptomycin) - act at 30S, cause misreading of mRNA Slide 15
Injury to Bacteria Plasma Membrane P olypeptide antimicrobials
Polymyxin B Colistin Affect permeability of cells Result in leakage
of macromolecules and ions essential for cell survival Slide 16
Inhibition of Bacteria DNA/RNA Synthesis Ciprofloxacin
(fluoroquinolone) - bind and interfere with DNA gyrase involved in
DNA supercoiling Metronidazole - breaks DNA strand Rifampin - binds
to DNA dependent- RNA polymerase to inhibit mRNA synthesis Slide 17
Inhibition Bacteria Folate Synthesis Antimetabolite - closely
resemble normal substrate (analogue), competes for enzyme Both
sulfonamide and trimethoprim interfere with folic acid pathway
Often in single pill used in combination drug therapy:
Trimethoprim- Sulfamethoxazole (TMP-SMX, Bactrim) Broad spectrum
antimicrobial Slide 18 Inhibition of Bacteria Enzymatic Activity
Nitrofurantoin - targets synthesis of several bacterial enzymes and
proteins; may also directly damage DNA Isoniazid - structural
analogue of vitamin B 6 ; inhibits synthesis of mycolic acid of
Mycobacteria cell wall Ethambutol - inhibits incorporation of
mycolic acid into Mycobacteria cell wall Slide 19 Summary: Bacteria
Antimicrobial Slide 20 Antifungal Drugs Nystatin and amphotericin B
combine with sterols to disrupt fungal plasma membrane Effective
because animal sterols are mostly cholesterol while fungal
membranes contain mainly ergosterol against which the drugs target
Ketoconazole (imadazole) - interfere with sterol synthesis
Griseofulvin - binds to keratin on skin, hair, and nails;
interferes with mitosis and fungal reproduction Slide 21 Antiviral
Drugs: Nucleoside Analogue In viral nucleic acid, analogue insert
in place of normal nucleoside Nucleic acid synthesis stops
Nucleoside analogue binds more strongly with viral enzyme than host
cell enzyme Example: acyclovir for herpes virus; also several
nucleoside analogues for HIV infection Slide 22 Other Antiviral
Drugs Interferon protein made by host cell for first line of
antiviral defense; cloned by recombinant DNA technology, treatment
for severe and chronic virus infections Tamiflu, Relenza interfere
with release of influenza virus from host cell Protease inhibitors
interfere with proteolytic cleavage of HIV polyproteins into
individual proteins, stops replication process Anti-sense or siRNA
(small, interfering RNA) experimental antiviral drugs, inhibits
mRNA translation Slide 23 Antimicrobial Susceptibility Testing
Important as different MO species and strains have different degree
of susceptibility to different antimicrobials Susceptibility of MO
to antimicrobial may change with time, even during course of
antimicrobial therapy Slide 24 Drug Sensitivity Test: Diffusion
Test Kirby-Bauer Test standardized lab test with antibiotic
impregnated disk, diffuses out in a concentration gradient, measure
zone of inhibited bacterial growth E Test utilizes plastic coated
strip containing gradient of antibiotic that diffuses out, allows
estimate Minimal Inhibitory concentration (MIC) that prevents
visible bacterial growth Slide 25 Drug Sensitivity Test: Test Tube
Dilution Broth Dilution Test measures more accurately serial
antibiotic dilutions in broth test tube for MIC, followed by
plating for Minimal Bacteriocidal Concentration (MBC) Slide 26
Antibiotic Resistance Presently a common occurrence Bacterial drug
resistance requires interruption or disturbance of the steps for
antimicrobial action Slide 27 Antibiotic Resistance Intrinsic
resistance - normal genetic, structural, or physiologic state of
MO; considered natural and inherited characteristic associated with
majority of strains of bacterial group Acquired resistance -
altered cellular physiology and structure caused by changes in a MO
genetic makeup; may be a trait associated with only some strains of
bacterial group Slide 28 Acquired Antibiotic Resistance Acquisition
of genes from other MOs via gene transfer mechanisms (i.e.,
resistance plasmids) A combination of mutational and gene transfer
events Slide 29 Pathways of Antibiotic Resistance Slide 30
Enzymatic Degradation: Penicillinase Resistance to penicillin and
other beta-lactam antibiotics Production of an enzyme that breaks
beta-lactam ring Slide 31 Gram(+) MO Resistance to Beta- lactam
Antibiotics Enzymatic degradation MO produces beta- lactamase,
cleaves ring structure of antibiotic Altered antimicrobial target
MO mutation of penicllin binding proteins (PBP) so antibiotic no
longer binds to it Slide 32 Gram(-) Resistance to Beta-lactam
Antibiotics Decrease uptake - of antibiotic Enzymatic degradation
of antibiotic Altered antimicrobial target - PBP Slide 33 Slide 34
Dissemination of Antimicrobial Resistance Slide 35 Prevention of
Bacterial Antimicrobial Resistance Use antimicrobial drugs only
when necessary Finish prescribed course of antimicrobial Use drugs
in combination; microbe less likely to develop resistance to two
drugs at the same time: Consider synergistic effects Consider
antagonistic effects
