antibiotic resistance the miracle revoked? wilson “bill” muse 10/29/2009
TRANSCRIPT
Antibiotic Resistance
The Miracle Revoked?
Wilson “Bill” Muse10/29/2009
Eukaryotes
Fungi
AzolesAllylamines
CycloheximidePolyenesPolyoxins
Nucleic acidanalogs
Echinocandins
Bacteria
Mycobacteria Gram-negativeBacteria
Gram-positiveBacteria
Obligately parasitic Bacteria
Chlamydia Rickettsia
Viruses
RNAviruses
DNAviruses
Tobramycin Penicillins
Streptomycin
SulfonamidesCephalosporins
Quinolones
Isoniazid
Tetracycline
VancomycinDaptomycin
Platensimycin
Polymyxins
Nucleoside analogsInterferon
Nonnucleosidereverse-transcriptase
inhibitorsProtease inhibitorsFusion inhibitors
The Miracle of Antibiotics
Classes of antibiotics• Aminoglycosides
• Tetracyclines
• Sulfonamides
• Quinolones
• Polypeptides
• B-lactams
• Macrolides
• Glycopeptides
• Cephalosporins
Antibiotic modes of action5 main targets
• 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
CycloserineVancomycinBacitracinPenicillinsCephalosporinsMonobactamsCarbapenems
Folic acid metabolism
Quinolones Nalidixic acid
DNA gyrase
CiprofloxacinNovobiocin
TrimethroprimSulfonamides
DNA
THF
DHF
mRNA
50
30 30
50
Ribosomes
30
50
Cytoplasmic membranestructure and function
PolymyxinsDaptomycin
PABA Cytoplasmicmembrane
Cell wallPlantensimycin
Lipidbiosynthesis
Protein synthesis(tRNA)
MupirocinPuromycin
TetracyclinesSpectinomycinStreptomycinGentamicinKanamycinAmikacinNitrofurans
Lincomycin
Protein synthesis(30S inhibitors)
Erythromycin (macrolides)ChloramphenicolClindamycin
RifampinStreptovaricins
DNA-directed RNA polymeraseRNA elongation
Actinomycin
Protein synthesis(50S inhibitors)
Antibiotics: Mechanisms of ActionInhibition of Cell Wall Synthesis
-some antibiotics prevent peptidoglycan formation
Examples: vancomycin, amoxicillin, ampicillin, penicillin
Cross-linking of peptidoglycan
transpeptidase
C NH CH CH C
O
O C N CH
CH3
CH3
COOH
S
STRUCTURE OF PENICILLIN
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
• Modify antibiotic
• Pump it out
• Alter the target site
• Bypass the pathway
C NH CH CH C
O
O C N CH
CH3
CH3
COOH
S
Site of penicillinase action.Breakage of the B-lactam ring.
Alter the drug to render ineffective
ex: anti-streptomycin
ex. anti-sulfanilamides
ex: anti-B-lactams
ex: anti-tetracyclins quinolines
Mechanisms of antibiotic resistance
•Efflux Pumps•Hydrolysis•Reduced Uptake•Sequestering•Enzymatic Modification
mechanismsThe 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
• 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