Lecture 28: Antibiotics

Question 1

What is the definition of an antibiotic?

Answer 1

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

Question 2

What is bacteria?

Answer 2

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

Question 3

What are the criteria for bacteria classification?

Answer 3

1. aerobic versus anaerobic
2. shapes (rod, spheres, or spirals)
3. Cell wall components (gram negative or gram positive)

Question 4

What are the two types of bacteria cell wall?

Answer 4

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

Question 5

What are the components of a bacterial cell membrane?

Answer 5

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

Question 6

What does the peptidoglycan structure consist of?

Answer 6

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)

Question 7

What is pathogenic bacteria?

Answer 7

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

Question 8

What are diseases caused by pathogenic bacteria?

Answer 8

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)

Question 9

How have antibiotics changed human health and survival?

Answer 9

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

Question 10

What is the spectrum of activity?

Answer 10

can be narrow or broad spectrum depending on the number of different bacterial species against which they exhibit useful activity

Question 11

What is bacterial sensitivity?

Answer 11

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

Question 12

What is the ability to penetrate?

Answer 12

delivery of antibiotic to site of infection is most difficult challenge of antibiotic delivery

Question 13

What is the therapeutic index?

Answer 13

ratio of the minimum concentration likely to produce an adverse effect to the minimum concentration needed to produce a desired effect

Question 14

What are the four classes of antibiotics?

Answer 14

cell wall inhibitors
folic acid
DNA synthesis inhibitors
protein synthesis inhibitors

Question 15

What is penicillin?

Answer 15

cell wall inhibitor

penicillin first antibiotic commercially developed

discovered by Alexander Fleming in 1928

product of the fungus Penicillium notatum

Question 16

What are cephalosporins?

Answer 16

cephalosporins derived from the fungus Acremonium; discovered in 1945

Question 17

What are cell wall inhibitors?

Answer 17

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)

Question 18

What are beta-lactamases?

Answer 18

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

Question 19

What are beta-lactamase inhibitors?

Answer 19

(i.e. clavulanic acid)

are potent inhibitors of beta-lactamases used in combinations to protect hydrolyze penicillins from inactivation

Question 20

What is vancomycin?

Answer 20

vancomycin is not a beta-lactam, but also inhibits peptidoglycan cross linking

produced in nature by Actinobacteria species, Amycolatopsis orientalis, commonly found in soil

Question 21

What are folic acid inhibitors?

Answer 21

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)

Question 22

What are sulfonamides and trimethoprim?

Answer 22

resemble PABA and dihydrofolic acid, respectively, and interfere with PABA metabolic pathways

usually given together to block sequential steps in synthesis of folic acid

Question 23

What are protein synthesis inhibitors?

Answer 23

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

Question 24

What are three types of protein synthesis inhibitors?

Answer 24

Chloramphenicol and Macrolides bind to the 50S subunit and block transpeptidation

Tetracyclines bind to the 30s subunit and prevent binding of incoming tRNA

Question 25

What are aminoglycosides?

Answer 25

aminoglycosides bind the 30s ribosomal subunit

block the initiation of the complex

cause misreading of the code of the mRNA template

inhibit translocation

Question 26

What is antibiotic specificity?

Answer 26

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)

Question 27

What is bacterial resistance?

Answer 27

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

Question 28

What are the four classifications of bacterial resistance?

Answer 28

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

Question 29

What are gastrointestinal distress side effects of antibiotics?

Answer 29

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

Question 30

What are other general side effects of antibiotics?

Answer 30

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