antibiotic mechanisms of action and resistance
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Antibiotic Mechanisms of Action and Resistance. MLAB 2434 – Microbiology Keri Brophy-Martinez. Overview. Antimicrobial Therapy Broad term for use of chemical compounds to treat diseases caused by microorganisms - PowerPoint PPT PresentationTRANSCRIPT
Antibiotic Mechanisms of Action and Resistance
MLAB 2434 – Microbiology Keri Brophy-Martinez
Overview
Antimicrobial TherapyBroad term for use of chemical
compounds to treat diseases caused by microorganisms
Antimicrobial agents used to treat infections are directed by antimicrobial susceptibility testing (AST)
Targets specific body sites or specific characteristics of microbes
Agents
Antimycobacterials Treat mycobacterial diseases
Antifungals Treat fungal disease
Antiprotozoals Tread protozoal disease
Antivirals Treat viral disease
Antibiotics Treat bacterial disease
Antibiotics
Antibiotics are naturally occurring substances produced by a fungus or bacteria
Used to treat bacterial infections Alternate Forms
Synthetic• Totally manufactured or artificial
• Semi-synthetic compounds• Naturally occurring substances that have
been chemically altered
Definitions
BacteriocidalKills the bacteria
BacteriostaticInhibit microbial growth
Definitions (Cont’d)
Spectrum of activity Range of susceptible organisms
•Narrow-spectrum• Kill either Gram positive or Gram
negative organisms• Organism specifc
•Broad-spectrum• Kill both Gram positive and Gram
negative organisms• Extensive
Empirical therapy Initiation of therapy prior to organism ID
Definitions (Cont’d)
Additive Effects Combining two antimicrobials causes twice
the effect of the two drugs by themselves Indifference
No effect of combining antimicrobial therapies
Synergy Combined effect is greater than the two
individual effects added together Antagonism
One drug counteracts the other
Antimicrobial Agents:Factors to Consider
What is the targeted bacteria? Where is it located? Can the
antimicrobial reach that site in sufficient concentration?
Can the antimicrobial be retained in the body long enough to be effective?
What are the side effects? How is it excreted?
What is the cost?
Antimicrobial Categories
Mechanisms of actionEffects on Cell Wall SynthesisInterruption of Cell Membrane
Structure and FunctionInhibition of Protein SynthesisInhibition of Folate SynthesisInterference with Nucleic Acid
Metabolism
Effects on Cell Wall Synthesis Cell wall protects the bacteria
cytoplasmic membrance Cell wall primarily composed of a
peptidoglycan layer Inactivating or interfering with
enzymes that synthesize the cell wall can destroy the bacteria
β-Lactam Antibacterial Agents
Effect cell wall synthesis
Sizable portion of antibacterial agents used today
Includes penicillins, monobactams, and carbapenems, and cephalosporins
β-Lactam Antibacterial Agents: Overview
Bind specific enzymes known as penicillin-binding proteins (PBPs)PBPs mediate peptidoglycan
cross-linking If PBPs are bound by the beta-lactam,
the cross-linking of the cell wall is incomplete, results in cell death
β-Lactam Antibacterial Agents Penicillins
Simple penicillins are effective against many streps, Neisseria, Pasteurella, and a number of anaerobes
Monobactams Limited to aerobic Gram negative bacilli
Carbapenems Broadest antimicrobial spectrum Effective against gram positive and negative
organisms, and anaerobes Resistant to beta-lactamase
Cephalosporins Classified by their spectrum of activity and are
spoken of in terms of “generations”
Generations of Cephalosporins
First-generation Have good GP and GN activity
Second-generation Have better GN, and anerobes activity
Third-generation Better with Enterobacteriaceae and Pseudomonas
spp. Fourth –generation
Effective against GNR that are resistant to 3rd generation cephalosporins
Fifth-generation Spectrum of activity includes the 3rd and 4th
generation
β-Lactam/β-Lactamase Inhibitors
Combination of a β-lactam and a β-lactamase inhibitor act in synergyBind to beta-lactamase produced
by certain microbes β-Lactamase Inhibitors
Offer no antibacterial activity by themselves• Examples include: clavulanic acid,
sulbactam, tazobactam
Effects on Cell Wall Synthesis Glycopeptides
Bind certain amino acids and inhibit enymes in the developing peptidoglycan layer
Vancomycin• Most clinically important• Effective against MRSA, other GP
organisms, and organisms resistant to penicillin
Interruption of Cell Membrane Structure and Function Damages the cytoplasmic membrane of
the organism Bacitracin
Prevents the addition of peptidogylcan to the cell wall
Disrupts the cell membrane Primarily effective against GP organism Because of toxicity, these are limited
to topical medications (ex. Neosporin, etc.)
Interruption of Cell Membrane Structure and Function Polymyxins
Bind to outer surface of cell membrane, affecting phospholoid
Leads to leakage of intracellular contents and cell death
Effective against gram negative bacteria
Inhibition of Protein Synthesis These antimicrobials bind to ribosomal
subunits This binding is either irreversible,
resulting in cell death(bactericidal), or reversible, resulting in bacteriostatic effects
AntibioticsAminoglycosides, tetracyclines,
macrolides, clindamycin chloramphennicol, and oxazolidinone
Antibiotics of Protein Synthesis Inhibition Aminoglycosides
BactericidalUsed primarily against GN
bacteria
Antibiotics of Protein Synthesis Inhibition Tetracyclines
BacteriostaticBroad spectrumEffective against GP and GN
organismsTetracycline is NOT used in young
children or in pregnancy, as it affects tooth and bone development
Antibiotics of Protein Synthesis Inhibition Macrolides
Bacteriostatic Broad spectrum Effective against GP and some GN
organisms, spirochetes, Mycoplasma, Legionella, and Chlamydia
Agents include: erythromycin, azithromycin, clarithromycin
Antibiotics of Protein Synthesis Inhibition
Clindamycin Bacteriostatic Excellent activity against aerobic
GP organisms Extremely potent against
anaerobes “D” test
• Detects resistance to clindamycin based on past treatment with erythromycin
Antibiotics of Protein Synthesis Inhibition Chloramphenicol
Bacteriostatic Has broad activity but is extremely
toxic
Oxazolidinone Linezolid Effective against MRSA, VRE, and
mycobacteria
Inhibition of Folate Synthesis
Folic acid pathway provides essential precursor molecules for DNA synthesis
Antibiotics can block steps in this pathway resulting in cell death
Agents: sulfonamides, trimethoprim Used in combination Active against broad spectrum,
including GP and GN organisms, except for P. aeruginosa
Interference with Nucleic Acid Metabolism Interfere with either DNA or RNA
metabolism Inhibit enzymes required in the
replication process Agents:
quinolones/fluoroquinolones, rifamycins
Antibiotics of Nucleic Acid Metabolism Interference
RNA Synthesis Interference Rifampin
Mainly used for M. tuberculosis and M. avium complex
Has a broad spectrum of activity
Antibiotics of Nucleic Acid Metabolism Interference
DNA Synthesis Interference Quinolones/Fluoroquinolones
• Bactericidal• Used to treat GN organisms• Agents- ciprofloxacin, levofloxacin
Metronidzole • Activates under anaerobic conditions• Effective against anaerobes and protozoa,
bacterial vaginosis Nitrofurantoin
• Used against GN and GN organisms• Concentrates well in urine
Mechanisms of Antimicrobial Resistance Modify target
If target is altered, reduction or prevention of antimicrobial binding can occur
End result- antimicrobial is ineffective How does the microbe modify the
target?• Chromosomal mutations• Transposons• Plasmids
Mechanisms of Antimicrobial Resistance Inactivation of Antimicrobial
AgentGenes of the microbe encode
enzymes that convert active antimicrobial agents to an inactive form• Encoding of enzymes via chromosomal
or plasmid-mediated genes• Example: beta-lactamase producing
organisms
Mechanisms of Antimicrobial Resistance Blockage of antimicrobial entry
into the cell Mechanisms
Decreased permeabilityDecreased uptakeIncreased ability to pump
antimicrobial out of cell
References
Kiser, K. M., Payne, W. C., & Taff, T. A. (2011). Clinical Laboratory Microbiology: A Practical Approach . Upper Saddle River, NJ: Pearson Education.
Mahon, C. R., Lehman, D. C., & Manuselis, G. (2011). Textbook of Diagnostic Microbiology (4th ed.). Maryland Heights, MO: Saunders.
http://www.parn.org.pk/index_files/D.test.html