Ch.20 - ANTIMICROBIAL AGENTS PDF

Preview

Summary

ANTIMICROBIAL AGENTS...

Description

ANTIMICROBIAL AGENTS (Chapter 20) Inhibition (Injury to) of: 





 

Cell wall 1. Penicillin(s) 2. Cephalosporins Protein synthesis 1. Chloramphenicol 2. Erythromycin 3. Tetracycline 4. Streptomycin Nucleic acid 1. Rifampin 2. Quinolones and fluoroquinolones Plasma membrane 1. Polymyxin B Metabolism 1. Sulfanilamide 2. Trimethoprim

Chapter 20: Antimicrobial Agents Antimicrobial agents function in one of five ways: 





 



Inhibition of cell wall synthesis o Penicillins o Cephalosporins Inhibition of protein synthesis o Chloramphenicol o Erythromycin o Tetracyclines o Streptomycin Inhibition of nucleic acid replication and transcription o Quinolones o Rifampin Injury to plasma membrane o Polymyxin B Inhibition of synthesis of essential metabolites o Sulfanilamide o Trimethoprim

Best option is to go for the cell wall first, then  protein synthesis  nucleic acid  plasma membrane  metabolism

Antibiotics   

Antibiotic – A substance produced by microorganisms that in small amounts inhibits another microorganism  Endospore-forming bacteria such as bacillus and molds Broad-Spectrum Antibiotics – Antibiotics that affect a broad range of gram-positive or gramnegative bacteria Porin channels in G- bacteria influence the selective toxicity of antibacterial drugs o Drugs that pass through the porin channels must be relatively small and hydrophilic

The Action of Antimicrobial Drugs  

Bactericidal – Kill microbes directly Bacteriostatic – Prevent microbes from growing o The host’s own defenses, such as phagocytosis and antibody production eliminate the bacteria present

CELL WALL   

First, and easiest way is attacking the cell wall Peptidoglycan is found only in bacterial cell walls Destroy the P of peptidoglycan  causing cell death o Penicillin(s) o Cephalosporins

Penicillin(s)   



Made from mold 50 related species of penicillin molecules Tied together by the nucleus o All have a common nucleus Beta-lactam ring o “Active binding ring” – preserved to maintain the antimicrobial effect The side chains are what is different o E.g., PenG vs PenV  Only difference is the presence of an -O- group  Change in how it is taken  G – has to be taken by injection  V – can be taken orally





 



Penicillins prevent the cross-linking of the peptidoglycans, which interferes with the final stages of the synthesis of the cell walls, primarily gram-positive bacteria  Attack PG  P part  Cell death Penicillinases effect both PenG and PenV  is responsible for antibiotic resistance o Opens up the nucleus and destroys them

Adverse effects (Contraindicator) o Known to cause allergies Disadvantages of natural penicillin o Narrow spectrum o B-lactam ring can be attacked by penicillinases of bacteria (mainly staphylococcus species) Semi-Synthetic Penicillin o Counteracts the disadvantages of natural penicillin o Made in a lab  usually through modification of natural penicillin  They can interrupt synthesis of penicillin by Penicillium and obtain only the common B-lactam nucleus for use  They remove the side chains from the completed natural molecules then chemically add other side chains that make them more resistant to penicillinase

o

o

o

 Difficult to synthesize (from a mold)  Broad spectrum  Can affect both gram positive and gram negative Methicillin  Resistance of staphylococcal infections to penicillin soon became a problem because of a plasmid-borne gene for B-lactamase  Methicillin was developed to counteract this  Methicillin-Resistant Staphylococcus Aureus (MRSA)  When staphylococcal mutated again and became resistant to Methicillin Oxacillin  Narrow spectrum  Only gram-positives  Resistant to penicillinase Ampicillin  Extended spectrum  Many gram-negatives

Cephalosporins  

 



Kills the Peptidoglycan (Peptido- portion) Made from cephalosporium mold  very expensive to produce o Used regardless of cost when treating meningitis  Use third generation of cephalosporin  Generation = semi-synthetic  With each generation, you have made a better spectrum Their B-lactam ring differs slightly from that of penicillin, but bacteria have developed Blactamases that inactivate them Semi-Synthetic o Expensive o Grouped into 5 generations (Worse to better) 1. Primary against gram-positive bacteria 2. More extended gram-negative spectrum 3. Most active against gram-negative bacteria  P. aeruginosa 4. Requires injections; most extended spectrum of activity 5. Effective against gram-negative bacteria and MRSA Adverse Effect o Mild diarrhea o Rash o Slight fever o Slight cramps

Comparison of Penicillin and Cephalosporin

PROTEIN SYNTHESIS    

Chloramphenicol Erythromycin Streptomycin Tetracycline

Chloramphenicol 



 

Attacks protein synthesis o Shuts down protein synthesis at the level of ribosomes o Attacks the large subunit of the ribosome complex o Attacks the 50s portion (where peptide bonds are formed) of the ribosome used in protein synthesis o Inhibits peptide bond formation  protein cannot be completed  cell death Simple structure o Found in nature o Easily synthesized in labs  Much lower cost o Can penetrate very well – Can penetrate the blood-brain barrier Drug of choice for meningitis Adverse effect o Aplastic Anemia  Rare but fatal – 1/1000  Suppresses the formation of red and white blood cells

Erythromycin 



 



 

Belong to the group of Macrocytes o Large ring structure o Cannot be synthesized in a LAB Mechanism of action: Completely stops the movement of mRNA through the ribosome o Attach to the large subunit of the ribosome (50s) o Stops translocation Ineffective against gram-negative bacteria Drug of choice when o Allergic to penicillin  One of the least toxic drugs around o For young children  Can be made in a (flavored) syrup form  Easy to administer Adverse effects o Mild GI discomfort (particularly in children) – 2-3% of the population overall ‘ o Mild fever Recommended for: pneumonia, strep throat Azithromycin: Used for chlamydia o Broader antimicrobial spectrum o Penetrates tissues better

Streptomycin  

 

Belong to the group: Aminoglycosides o All have amino sugars in them linked by glycoside bonds Aminoglycosides  change the shape of the 30s subunit o Streptomycin o Neomycin o Gentamycin One of the oldest drugs Mechanism of action: Attacks the smaller subunit (30s) of the ribosome o Changes the shape of the mRNA



Ribosome will read up until the point where the shape has changed and then leave prematurely  Results in an incomplete protein being made  an aberrant protein OR  Ribosome will jump the changed portion of the mRNA and continue transcription  Results in an aberrant protein  Was the drug of choice for diseases such as tuberculosis o Not anymore  TB has developed a lot of resistance o Can still be used in a reduced dosage and in combination with other drugs – just not by itself  Adverse effects o Resistance o Kidney failure – Nephrotoxicity o Damage to auditory nerve – Deafness Tetracycline 







Complex  Generated in nature or semisynthetic o Semi: longer retention in the body  produces longer effects in the body  Doxycycline  Used to treat: Nongonococcal Urethritis (NGU), Pelvic Inflammatory Disease (PID)  Minocycline o Pure Mechanism of action o Attaches to the 30s (smaller) subunit o Blocks the reading site of the codons – blocks the docking site were tRNA docks and forms a partial bond  Prevents tRNA from reading the mRNA Has the broadest spectrum of activity o Can be used for many things  Gram +  Gram –  Rickettsia  UTIs  STDs  Chlamydia, syphilis, gonorrhea  Mycoplasma  Mycoplasma pneumoniae  Animal farmers – used to keep antimicrobial agents at bay and to increase weight gain Adverse effects o Severe diarrhea – kills normal microbiota in the body and allows for invading organisms like fungi  causes havoc o Should be avoided during pregnancy  Causes liver failure in the mother o In children  causes brown spots on teeth o Affects bone growth – Abnormal fetal bone growth and fetal skull formation  Has an affinity for binding to calcium

NUCLEIC ACID SYNTHESIS 

Drugs that block bacterial topoisomerase or RNA polymerase o Rifamycin o

Quinolones and Fluoroquinolones

Rifamycin 

Drug of choice for o Mycobacterium tuberculosis (Tuberculosis) o Mycobacterium leprae (Leprosy)  Completely stops the process of transcription o Inhibits RNA polymerase  Thereby inhibiting mRNA transcription  Has gradually replaced streptomycin as a drug of choice over the years o Penetrates tissues well, and can reach CSF  Taken orally  requires low dosage to avoid adverse effects  Adverse effects o Mild hepatotoxicity (liver damage) o Dangerous to pregnancy Quinolones and Fluoroquinolones  Uses: o UTIs o Legionella  Legionella pneumophila  Pontiac fever  Legionaries disease o Anthrax  Fluoroquinolones o Inhibit DNA gyrase  inhibit the replication of DNA o FLOURO Is a quinolone  Addition of fluoride ion  Commercial name = CIPRO  Increased penetration over the old version  Increased potency  Can be taken orally  Adverse effects: o Attaches to bones o Attaches to cartilage  Affects cartilage development  Avoid administering to:

o o o o

Children Teenagers Pregnant mothers The elderly

PLASMA MEMBRANE 

Changes permeability in plasma membrane  loss of important metabolites from the cell o Polymyxin B o Amphotericin B

Polymyxin B     

Looks and behaves somewhat similar to Amphotericin B Anti-bacterial agent drug Ruptures the bacterial plasma membrane  contents of the cell leak out  cell death Used for: Pseudomonas infections  especially on burn wounds MUST be given as an ointment  can only be given topically NOT systemically (as a pill/ingested) o Is very toxic  Adverse effects o Nephrotoxicity o Kidney failure Amphotericin B 

Anti-fungal drug

ESSENTIAL ANTIMETABOLITES  

Sulpha drugs (sulfanilamide, sulfamethoxazole) Trimethoprim COMPETITIVE INHIBITORS

  

Sulpha drugs (Sulfanilamide) Trimethoprim Both acts as competitive inhibitors



  







Both attack the PABA chain of enzymatic reaction o PABA eventually becomes Folic Acid o Folic Acid functions as a coenzyme for the synthesis of proteins, DNA, and RNA o If folic acid production is prevented  effectively killed bacteria Sulpha drugs – destroys PABA earlier in the chain Trimethoprim – destroys PABA later in the chain Used for o UTIs o Infections in burn patients (silver sulfadiazine) Adverse effects of Sulfa drugs o Light jaundice o Allergic response o Anemia o Dangerous in pregnancy – especially during the 3rd trimester Adverse effects of Trimethoprim o Jaundice o Allergic reactions o Anemia o Slightly less toxic than sulfa drugs Can combine sulfa drugs and trimethoprim synergistically o Allows for a broader spectrum of action o Reduces emergence of resistant strains

ANTIVIRAL DRUGS   

  

Are all synthetics Will not cure  Reduce the viral load  Will reduce the number of virions produced Are nucleosides (Nucleotide) analogs: Designed to mimic nucleotides in the body  Nucleotide: Base + Sugar + Phosphate  Nucleoside: Base + Sugar – Phosphate o Lack a phosphate In the body, they add the phosphate that was missing The drug then becomes a false nucleotide Inhibits DNA and RNA formation Drug Base Use Acyclovir Guanine Herpes-2, Herpes-3 (Shingles) Ganciclovir Guanine Herpes-5 Zidovudine Thymine HIV Thymine HIV, Hep B Lamivudin e



Acyclovir is taken orally



HAART Treatment (Highly Active, Antiretroviral Treatment) o

Attacks and mutates the nitrogen base

o

o

o

o

Zidovudine (ZVD) 

Thymine Analog



HAART drug  HIV

Lamivudine (3-TC) 

Cytosine analog



HAART Drug  HIV



Also used for Hep B

Acyclovir 

Guanine analog



Herpes 2 and 3

Ganciclovir 

Guanine analog



Herpes 5...