Lecture 28: Antibiotics Flashcards
What is the definition of an antibiotic?
antibiotics, strictly speaking, are soluble compounds that are produced and released by microorganisms and that inhibit the growth or kill other microorganisms
this narrow definition has been expanded by popular usage to include synthetically or semi-synthetically produced antimicrobial agents
What is bacteria?
bacteria are single cell organisms
among the first life forms to appear on Earth
present in most habitats (soil, water, acidic hot springs, deep within Earth crust)
symbiotic and parasitic relationship with plants and animals
What are the criteria for bacteria classification?
- aerobic versus anaerobic
- shapes (rod, spheres, or spirals)
- Cell wall components (gram negative or gram positive)
What are the two types of bacteria cell wall?
bacteria can have 2 different types of cell wall
this feature is used to classify bacteria into gram-positive bacteria and gram-negative bacteria
the names originate from the reaction of cells to the Gram stain, a long-standing test for the classification of bacterial species
What are the components of a bacterial cell membrane?
bacterial cell walls are made of polysaccharide chains called peptidoglycan
gram-positive bacteria possess a thick cell wall with many layers of peptidoglycan
gram-negative bacteria have a relatively thin cell wall with few layers of peptidoglycan surrounded by a second lipid membrane containing lipopolysacchardes and lipoproteins
most bacteria have the gram-negative cell wall
What does the peptidoglycan structure consist of?
peptidoglycan structure consists of glycan stands made of alternating N-acetylglucosamine (GlcNAc) and N-acetylmuramic acid (MurNAc) residues cross-linked by peptides
contribute to overall structure and shape of bacterium
individual strands are polymerized by enzyme glycosyltransferase (GT) into peptidoglycan chain
transpeptidase (TP) cross link the strands; TP is targeted by many antibodies (penicillin binding protein)
What is pathogenic bacteria?
we are covered in thousands of microbial species (called the normal flora), particularly in the skin, mouth, large intestine and genital
normal flora only cause trouble if immune systems are weekend or if they gain access to normally sterile part of the body (i.e. bowel perforation)
pathogens do not require that the host be immunocompromised or injured; they have developed highly specialized mechanisms for crossing cellular and biochemical barriers and for eliciting specific responses from host organism that contribute to the survival and multiplication of the pathogen
What are diseases caused by pathogenic bacteria?
food borne illnesses (Shigellosis, Campylobacter, Salmonella)
sexually transmitted diseases (Chlamydia, Syphilis)
skin infections (Impetigo, Staphylococcus aureus infections, Gum disease)
highly infectious diseases (Cholera, Diphtheria, Scarlet Fever, Typhoid Fever, Whooping Cough, Tuberculosis, Pneumonia)
How have antibiotics changed human health and survival?
prior to sulfonamides in the 1930s and penicillins in the 1940s, not uncommon for otherwise healthy individuals to die from infection that are today considered commonplace and nonthreatening
What is the spectrum of activity?
can be narrow or broad spectrum depending on the number of different bacterial species against which they exhibit useful activity
What is bacterial sensitivity?
sensitivity is measured by assessing the ability of bacterial strain to replicate following antibiotic exposure
bacteriocidal antibiotic leads to permanent loss of replicative ability
bacteriostatic antibiotic leads to temporary loss of growth and replication that return following the removal of antibiotics
What is the ability to penetrate?
delivery of antibiotic to site of infection is most difficult challenge of antibiotic delivery
What is the therapeutic index?
ratio of the minimum concentration likely to produce an adverse effect to the minimum concentration needed to produce a desired effect
What are the four classes of antibiotics?
cell wall inhibitors
folic acid
DNA synthesis inhibitors
protein synthesis inhibitors
What is penicillin?
cell wall inhibitor
penicillin first antibiotic commercially developed
discovered by Alexander Fleming in 1928
product of the fungus Penicillium notatum
What are cephalosporins?
cephalosporins derived from the fungus Acremonium; discovered in 1945
What are cell wall inhibitors?
penicillins and cephalosporins are called “beta lactams” because they have an unusual 4 member ring
inhibit cell wall synthesis by inhibiting an enzyme (DD-transpeptidase) responsible for cross-linking components of the cell wall (bacteriocidal)
DD transpeptidase is also called penicillin binding protein
were originally only effective against gram positive bacteria, but successive generations of cephalosporins have increased activity against gram negative bacteria (though still work better on gram positive bacteria)
What are beta-lactamases?
are bacterial enzymes (penicillinases, cephalosporinases) made by most staphylococci and many gram negative organisms that hydrolyze the beta-lactam ring of certain penicillins and cephalosporins; confer resistance
What are beta-lactamase inhibitors?
(i.e. clavulanic acid)
are potent inhibitors of beta-lactamases used in combinations to protect hydrolyze penicillins from inactivation
What is vancomycin?
vancomycin is not a beta-lactam, but also inhibits peptidoglycan cross linking
produced in nature by Actinobacteria species, Amycolatopsis orientalis, commonly found in soil
What are folic acid inhibitors?
bacteria use folic acid to synthesize nucleic acids that make up their DNA
para-aminobenzoic acid (PABA) is a nutrient obtained from the environment that is the precursor for folate in bacteria
eukaryotes also use folic acid to build nucleic acid, but can pull from environment (food)
What are sulfonamides and trimethoprim?
resemble PABA and dihydrofolic acid, respectively, and interfere with PABA metabolic pathways
usually given together to block sequential steps in synthesis of folic acid
What are protein synthesis inhibitors?
bacteria make protein from mRNA template within the bacterial 70s ribosomal complex
tRNA (t6) transfers an amino acid (numbered circle) to the growing amino acid chain (transpeptidation)
eukaryotes have an 80s ribosomal complex (60S and 40S subunits), so unaffected by protein synthesis inhibitors
What are three types of protein synthesis inhibitors?
Chloramphenicol and Macrolides bind to the 50S subunit and block transpeptidation
Tetracyclines bind to the 30s subunit and prevent binding of incoming tRNA
What are aminoglycosides?
aminoglycosides bind the 30s ribosomal subunit
block the initiation of the complex
cause misreading of the code of the mRNA template
inhibit translocation
What is antibiotic specificity?
why don’t antibiotics inhibit protein synthesis in human cells as well?
selectivity is provided by the differences in protein synthesis enzymes between humans and microorganisms, and the rapid growth of bacteria
e.g. Chloramphenicol specifically does not bind to the 80S ribosomal RNA of mammalian cells (only the bacterial 70S ribosomal subunit)
e.g. mammalian cells cannot synthesize folic acid from PABA (must get it from diet)
What is bacterial resistance?
resistance is the ability of the microbe to resist the effects of antibiotics
consequence of evolution via natural selection; antibiotic action is an environmental pressure; those bacteria which have a mutation allowing them to survive will live on to reproduce
What are the four classifications of bacterial resistance?
drug inactivation or modification: i.e. beta lactamases are enzymes produced by bacteria that inactivate antibiotics
alteration of binding site: alteration of penicillin binding proteins in methicillin resistant staphylococcus (MRSA)
alteration of metabolic pathways: sulfonamide resistant bacteria begin to use preformed folic acid from the environment rather than making it from PABA
reduced drug accumulation: develop efflux pumps to actively remove antibiotic from bacterial cell
What are gastrointestinal distress side effects of antibiotics?
antibiotic therapy alters the bacterial environment of the body
loss of normal intestinal flora produces diarrhea or GI discomfort with a number of antibiotics
probiotic products, including active culture yogurt, may be used as adjunctive therapy to minimize GI effects
What are other general side effects of antibiotics?
adverse skin reactions, ranging from mild rash to photosensitivity
many antibiotics should be accompanied by photoprotection because sunscreens can prevent adverse skin reactions
Stevens-Johnson syndrome and toxic epidermal necrolysis are rare conditions in which the skin becomes detached from the underlying tissue and sloughs off the body
