Transcript Antibiotic Resistance

Antibiotic Resistance
The Miracle Revoked?
Wilson “Bill” Muse
10/29/2009
The Miracle of Antibiotics
Bacteria
Eukaryotes
Fungi
Mycobacteria
Gram-negative
Bacteria
Tobramycin
Azoles
Allylamines
Cycloheximide
Polyenes
Polyoxins
Nucleic acid
analogs
Echinocandins
Streptomycin
Obligately parasitic Bacteria
Gram-positive
Bacteria
Chlamydia
Penicillins
Sulfonamides
Cephalosporins
Quinolones
Rickettsia
Viruses
RNA
viruses
DNA
viruses
Nonnucleoside
reverse-transcriptase
inhibitors
Protease inhibitors
Fusion inhibitors
Tetracycline
Isoniazid
Polymyxins
Vancomycin
Daptomycin
Platensimycin
Nucleoside analogs
Interferon
Classes of antibiotics
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Aminoglycosides
Tetracyclines
Sulfonamides
Quinolones
Polypeptides
B-lactams
Macrolides
Glycopeptides
Cephalosporins
Antibiotic modes of action
5 main targets
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Prevent cell wall synthesis (B-lactams)
Disrupt membrane function (polymyxins)
Prevent protein synthesis (chloramphenicols)
Prevent nucleic acid synthesis (quinolones)
Disrupt metabolic pathways (sulfanilamides)
Cell wall synthesis
Cycloserine
Vancomycin
Bacitracin
Penicillins
Cephalosporins
Monobactams
Carbapenems
Quinolones
DNA gyrase
RNA elongation
Nalidixic acid
Ciprofloxacin
Novobiocin
Actinomycin
DNA-directed RNA polymerase
Rifampin
Streptovaricins
Protein synthesis
(50S inhibitors)
Erythromycin (macrolides)
Chloramphenicol
Clindamycin
Lincomycin
DNA
Folic acid metabolism
Trimethroprim
Sulfonamides
THF
mRNA
Protein synthesis
(30S inhibitors)
Ribosomes
DHF
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30
50
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30
Cytoplasmic membrane
structure and function
Polymyxins
Daptomycin
Lipid
biosynthesis
PABA
Plantensimycin
Cytoplasmic Cell wall
membrane
Tetracyclines
Spectinomycin
Streptomycin
Gentamicin
Kanamycin
Amikacin
Nitrofurans
Protein synthesis
(tRNA)
Mupirocin
Puromycin
Antibiotics: Mechanisms of Action
Inhibition of Cell Wall Synthesis
-some antibiotics prevent peptidoglycan formation
Examples: vancomycin,
amoxicillin, ampicillin,
penicillin
Cross-linking of peptidoglycan
transpeptidase
STRUCTURE OF PENICILLIN
O
S
C
NH
CH
O
C
CH
N
CH3
C
CH
CH3
COOH
Antibiotics: Mechanisms of Action
Inhibition of Bacterial Protein Synthesis
- some antibiotics bind to the large or small subunit of the bacterial
ribosome
Examples: neomycin,
streptomycin,
azithromycin,
erythromycin, tetracycline
Binding and altering ribosome
structure
Aminoglycosides
neomycin
Mechanism of Action
• Once inside the cell…
– Bind 30S ribosomal
subunit
– Blocks binding of
aminoacyl-tRNA to
acceptor site on
mRNA-ribosome
complex
– Protein synthesis is
inhibited =
bacteriostatic effect
Summary of Targets
How Antibiotic Resistance
Happens
Overcoming the arsenal
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Modify antibiotic
Pump it out
Alter the target site
Bypass the pathway
Alter the drug to render ineffective
O
S
C
NH
CH
O
C
CH
N
CH3
C
CH
CH3
COOH
Site of penicillinase action.
Breakage of the B-lactam ring.
ex: anti-streptomycin
ex: anti-tetracyclins
quinolines
ex: anti-B-lactams
ex. anti-sulfanilamides
Mechanisms of antibiotic resistance
•Efflux Pumps
•Hydrolysis
•Reduced Uptake
•Sequestering
•Enzymatic Modification
mechanisms
The four main mechanisms by which microorganisms exhibit resistance to
antimicrobials are:
Drug inactivation or modification: e.g. enzymatic deactivation of Penicillin G in some
penicillin-resistant bacteria through the production of ß-lactamases.
Alteration of target site: e.g. alteration of PBP—the binding target site of penicillins—
in MRSA and other penicillin-resistant bacteria.
Alteration of metabolic pathway: e.g. some sulfonamide-resistant bacteria do not
require para-aminobenzoic acid (PABA), an important precursor for the synthesis of
folic acid and nucleic acids in bacteria inhibited by sulfonamides. Instead, like
mammalian cells, they turn to utilizing preformed folic acid.
Reduced drug accumulation: by decreasing drug permeability and/or increasing active
efflux (pumping out) of the drugs across the cell surface.[4]
There are three known mechanisms of fluoroquinolone resistance. Some types of efflux
pumps can act to decrease intracellular quinolone concentration. In gram-negative
bacteria, plasmid-mediated resistance genes produce proteins that can bind to DNA
gyrase, protecting it from the action of quinolones. Finally, mutations at key sites in
DNA gyrase or Topoisomerase IV can decrease their binding affinity to quinolones,
decreasing the drug's effectiveness.[5]
Tetracyclines
• Broad-spectrum activity
– Includes aerobic G+ and G, atypicals [Rickettsia spp,
treponema spp, chlamydia
spp, and others]
– Little to no effect on fungi
or viruses
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Tetracycline
Doxycycline*
Minocycline
Tigecycline
www.3dchem.com
Summary
• Bacteria have evolved ways to counteract
the effects of most antibiotics.
• They mutate to alter target sites or recruit
enzymes to degrade or pump out antibiotics
• They share their tricks with other bacteria
through gene transfer