Mechanism of Action of Antibiotics Flashcards
1
Q
Biochemical Basis of Antimicrobial Action
A
- bacterial cells grow and divide, replicating repeatedly to reach the large numbers present during an infection or on the surfaces of the body
- to grow and divide, organisms must synthesize or take up many types of biomolecules
- antimicrobial agents interfere with specific processes that are essential for growth and/or division
2
Q
Bactericidal
A
-chemotherapeutic agents that are capable of causing irreversible damage or death to the organism. These agents are independent of the host’s immune system in their action on the organism
3
Q
Bacteriostatic
A
-agents that inhibit that growth and/or reproduction of the infecting agent, but fail to actually kill the agent. These agents are dependent on the host’s immune system for the elimination of the microorganism
4
Q
Bactericidal vs Bacteriostatic
A
-bactericidal agents are more effective, but bacteruistatic agents can be extremely beneficial since they permit the normal defenses of the host to destroy the microorganisms
5
Q
MIC vs MBC
A
- MIC- minimal inhibitory concentration- represents the lowest concentration of the antibiotic which prevents the organisms from multiplying- not necessarily killing the organism
- MBC- minimal bacteriocidal concentratin- represents the lowest concentration which kills the organism- not relevant with bacteriostatic agents
- there is a much closer relationship between the MIC and MBC values for bactericidal drugs than for bacteriostatic drugs
6
Q
Structures of antibiotics
A
- B-Lactams- Beta-lectam ring (e.g. penicillins, cephalosporins)
- aminoglycosides- vary only by side chains attached to basic structure (e.g. gentamycin, tobramycin)
7
Q
Function of antibiotics
A
- how the drug works, its mode of action
- inhibition of cell wall synthesis (most common mechanism- largest class of antibiotics)
- inhibition of protein synthesis (second largest class)
- alteration of cell membranes
- inhibition of nucleic acid synthesis
- antimetabolite activity
8
Q
Ideal antibiotic
A
- selective target- target unique
- bactericidal- kills
- narrow spectrum- does not kill normal flora
- high therapeutic index- ratio of toxic level to therapeutic level
- few adverse reactions- toxicity, allergy
- various routes of administration- IV, IM, oral
- good absorption
- good distribution to site of infection
- emergency of resistance is slow
9
Q
Where will the new antibiotics come from?
A
- there is a relentless increase in bacterial resistance to currently available antibiotics
- fever new antibiotics are being developed than ever before
- only 8 new antibacterial medications have been developed since 1998
- old: natural products: penicillins, cephalosporins, aminoglycosides, tetracyclines, erythromycin, and related macrolides and vacnomycin and teicoplanin
- newer: synthetic antibacterials: the second line of antibiotic discovery has come from synthetic chemistry- this is, producing antibacterial agents from structures that are not found in nature
10
Q
Various antimicrobial agents interfere with
A
- cell wall synthesis
- ribosomal function (protein synthesis)
- plasma membrane integrity
- nucleic acid synthesis
- folate synthesis or other metabolic function
11
Q
Newer Classes of Antibiotics
A
- Lipoglycopeptides- RX gram positive complicated skin and soft tissue infections
- Cyclic Lipopeptides- RX gram positive infections- including MRSA
- Glycylcyclines- RX gram positive (MRSA), gram negatives
- Oxazolidinones- Rx MRSA and VRE
12
Q
Gram Positive and Gram Negative Cell Wall composition
A
- the gram-positive cell wall is composed of a thick, multilayered petidoglycan sheath outside of the cytoplasmic membrane
- the gram-negative cell wall is composed of an outer membrane linked by lipoproteins to thin, layer of petidoglycan
- the petidoglycan is located within the periplasmic space that is created between the outer and inner membranes
13
Q
The bacterial cell wall
A
-Peptidoglycan- a network of N-acetyl Glucosamine and N acetylmuramic acid connected by peptide bonds
14
Q
Inhibitors of Cell Wall Synthesis
A
- Beta lactams- penicillins, cephalosporins, monobactams, cerbapenems
- glycopeptides- vanomycin- gram positive only
- fosfomycin- UTI’s only
- Daptomycin- gram positive only, may be used against MRS, VISA, VRSA, VRE
15
Q
Beta- lactam antibiotics
A
- beta-lactam antibiotics are among the most commonly prescribed drugs, grouped together based upon a shared structural feature, the beta- lactam ring
- there are about 50 different B- lactams currently on the market
- they are all bactericidal
- they are non-toxic (can be administered at high doses)
- they are relatively inexpensive
- B-lactams are organic acids and most soluble in water
16
Q
Penicillin Binding Proteins
A
- a set of transpeptidases that catalyze the final cross-linking reactions of peptidoglycan synthesis
- found in quantities of several hundred to several thousand molecules per bacterial cell
- two types of PBPs, low molecular weight PBPs and high molecular weight PBPs
- the high MW PBPs- involved in different activities during peptidoglycan synthesis whereas the low PBPs function as D-alanine carboxypeptidases
- inactivation of low MW PBPs is not thought to affect the viability of the cell
17
Q
How Do B-lactam’s work
A
-binds to the active site of the transpeptidase enzyme that cross-links the peptidoglycan strands by mimicking the D-alanyl-D-alanine residues that would normally bind to this site
18
Q
Carbapenem B-Lactams
A
- B lactams with a broad spectrum of action
- effective on gram positives, except MRSA
- broad activity against gram negatives
- slightly different structure than the other B-lactams, make them much more resistant to B-lactamase hydrolysis such as ESBL producers
- wide diffusion in the body, especially in the CSF
19
Q
Glycopeptides and Lipoglycopeptides
A
- glycopeptide: vancomycin- act by binding to D-alanyl-D-alanine residues thus preventing the cross linking of the peptitoglycan sheets
- lipoglycopeptides- not FDA approved
20
Q
Inhibitors of Protein Synthesis
A
-tetracyclines
-aminoglycosides, macrolides, lincosamides,
phenicols
-ansamycins
-oxazolidinones
21
Q
Tetracyclines
A
- Bacteriostatic- broad spectrum
- primarily for treatment for Chlamydiae, Rickettsiae, and Mycoplasma
- not recommended for pregnant women and children because of toxicity on bones and teeth of the fetus
- glyclycyclines- new class, developed to overcome some of the more common tetracycline resistance mechanism
- short acting (tetracycline)
- intermediate (demeclocycline)
- long acting (doxycycline)
22
Q
Aminoglycosides
A
- Bind to the RNA of the 30S ribosomal subunit that affects all stages of normal protein synthesis- bacteriocidal activity- gentamycin, tobramycin
- renal and ototoxicity- need to monitor blood levels
23
Q
Macrolides, Lincosamides, Streptogramins, Ketolides
A
- bacteriostatic- their spectrum of activity is limited to gram positive cocci such as streptococci and staphylococci
- these antibiotics are also active against anaerobes
24
Q
Phenicols: Chloramphenicol
A
- very active against many gram-positive and gram-negative bacteria, chlamydia, mycoplasma, and Rickettsiae
- resticted use of extra-intestinal severe salmonella infection
- high toxicity, causes bone marrow aplasia and other hematological abnormalities
25
Oxazolidinones: Linezolid
- relatively new
- gram positive infections
- disrupts bacterial growth by inhibiting the initiation process in protein synthesis
- because the site of inhibition is unique to linezolid cross- resistance to other protein synthesis inhibitors has not yet been reported
- gram-negative bacteria appear to be naturally resistant
26
Rifampin
- bacteriostatic or bactericidal- depending on organism and concentration
- primarily gram positive organisms and some gram negatives
- used in combinations with other drugs to treat TB
- used to treat carriers of N. meningitidis
- used in combination with other antibiotics for severe Staphylcoccal infections including MRSA
27
Inhibitors of membrane function
- Lipopeptides- Polymyxins and Colistin
| - Cyclic Lipopeptides- Daptomycin- FDA approval for skin/skin structure infections
28
Antimetabolites: Folate Pathway Inhibitors
- folic acid is essential for the synthesis of adenine and thymine
- humans do not synthesize folic acid. Good selective target
- sulfonamides- bacteriostatic, treat UTIs
- trimethoprim-bactericidal (bactrim), broad spectrum, synergistic action
29
Sulfonamides
- pharmacokinetics- good urine solubility, high levels in urine
- clinical uses- UTI, patients allergic to penicillins, otitis media
- allergies may lead to Stevens- Johnson syndrome
- Kernicterus, Hemolytic anemia
30
Timethoprim/ Sulfamthoxazole Action
- the drug resembles a microbial substrate and competes with the substrate for the limited microbial enzyme
- the drug ties up the enzyme and blocks a step in metabolism
31
Inhibitors of Nucleic Acid Synthesis
- Quinolones
- Fluoroquinolones
- act by targeting topoisomerases which is responsible for cutting one of the chromosomal DNA strands at the beginning of the supercoiling process
32
Furanes: Nitrofurantoin
- inhibitor of nucleic acid synthesis
- broad spectrum, bactericidal, oral
- UTI caused by gram-negative and gram-positive organisms
- the drug works by damaging bacterial DNA. In the bacterial cell, nitrofurantoin is reduced by flavoproteins
- these reduced products are highly active and attack ribosomal proteins, DNA, respiration, pyruvate metabolism and other macromolecules within the cell
