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Flashcards in Mechanism of Action of Antibiotics Deck (32)

Biochemical Basis of Antimicrobial Action

-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



-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



-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


Bactericidal vs Bacteriostatic

-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



-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


Structures of antibiotics

-B-Lactams- Beta-lectam ring (e.g. penicillins, cephalosporins)
-aminoglycosides- vary only by side chains attached to basic structure (e.g. gentamycin, tobramycin)


Function of antibiotics

-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


Ideal antibiotic

-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


Where will the new antibiotics come from?

-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


Various antimicrobial agents interfere with

-cell wall synthesis
-ribosomal function (protein synthesis)
-plasma membrane integrity
-nucleic acid synthesis
-folate synthesis or other metabolic function


Newer Classes of Antibiotics

-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


Gram Positive and Gram Negative Cell Wall composition

-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


The bacterial cell wall

-Peptidoglycan- a network of N-acetyl Glucosamine and N acetylmuramic acid connected by peptide bonds


Inhibitors of Cell Wall Synthesis

-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


Beta- lactam antibiotics

-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


Penicillin Binding Proteins

-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


How Do B-lactam's work

-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


Carbapenem B-Lactams

-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


Glycopeptides and Lipoglycopeptides

-glycopeptide: vancomycin- act by binding to D-alanyl-D-alanine residues thus preventing the cross linking of the peptitoglycan sheets
-lipoglycopeptides- not FDA approved


Inhibitors of Protein Synthesis

-aminoglycosides, macrolides, lincosamides,



-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)



-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


Macrolides, Lincosamides, Streptogramins, Ketolides

-bacteriostatic- their spectrum of activity is limited to gram positive cocci such as streptococci and staphylococci
-these antibiotics are also active against anaerobes


Phenicols: Chloramphenicol

-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


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



-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


Inhibitors of membrane function

-Lipopeptides- Polymyxins and Colistin
-Cyclic Lipopeptides- Daptomycin- FDA approval for skin/skin structure infections


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



-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


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


Inhibitors of Nucleic Acid Synthesis

-act by targeting topoisomerases which is responsible for cutting one of the chromosomal DNA strands at the beginning of the supercoiling process


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