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Semisynthetic:
naturally produced
antibiotics that have Streptomyces coelicolor
Broad spectrum
Narrow spectrum
Question
Which of the following is likely NOT
associated with broad spectrum antibiotics?
Exit
Antiviral drug
Nucleoside, Nucleotide Analogs
Incorporated into DNA or RNA
Can stop nucleotides from being added or alter
base-pairing properties
Exit
Viral uncoating
Effective against
influenza A virus:
Amantadine
Rimantadine
Antifungal Drugs
Cell walls made of chitin
Fungal membranes have ergosterol as
opposed to cholesterol
Normal bacterial
cell wall
Growth
Penicillin binding
protein (PBP),
called
transpeptidase
Bacterial Cell Wall Synthesis
Integrity of
peptidoglycan is
compromised
Question
C NH CH CH
S
C
CH3
C N
lactamases O
CH COOH
-lactam ring
(a)
Cephalosporin
O S
R C NH CH CH CH2
C N C
O R
-lactam ring COOH
(b)
Carbapenems
Resist most -lactamases
Carbapenems effective against a wide range
Question about Frontline
Video
KPC stands for Klebsiella pneumonia
carbapenemase. What does carbapenemase
do?
A. Cleaves all beta lactam rings
B. Cleaves beta lactam ring of just carbapenem
C. Confers resistance to all antibiotics
D. None of the above
Non beta-lactam Cell Wall Inhibitors:
Vancomycin
Is a glycopeptide
Binds to side chain of NAM molecules to
block the addition of the new NAM
subunits to a pre-existing chain (ie chain
elongation)
Weakens cell wall, causes lysis
Mechanism of vancomycin action
NAM NAG
V crosslink
topical applications
Nucleic Acid Synthesis Inhibitors
Fluoroquinolones
Inhibit prokaryotic topoisomerases
o One type of topoisomerase, DNA
gyrase, is a common target
Ie Clindamycin
Ie Streptomycin
Lincosamides and macrolides
Bind to the 50S subunit
Block proper mRNA movement through
ribosome
Clindamycin is an example of a lincosamide
Drug
50S
mRNA
Aminoglycosides
Ie streptomycin
Bind to 30S subunit
mRNA is misread
Causes premature release of the ribosome
from the mRNA
Incorrect
amino acids
50S Ribosome
mRNA
Aminoglycoside
30S
drug
Tetracyclines
Bind to 30S subunit
Block docking site of tRNA
Tetracycline
drug
50S
mRNA
Would protein synthesis inhibitors
have side effects?
Prokaryotes have 70S ribosomes
Eukaryotes have 80S ribosomes
Normal microbiota
important Intestine Intestine
to maintain
intestinal
balance
Mutation
Bacterium receiving
Resistance genes
Evolution of Drug Resistance
Mutations and horizontal gene transfer
provide diversity
Exposure
To drug Continued
Exposure
To drug
(b) Most sensitive
(a) Microbial (c) Most new cells are
cells are eliminated
cells resistant, infection will
by drug early :
involved in no longer respond to
resistant cells survive
an infection and grow drug
Frontline video Question
Why are antibiotic resistant infections often
hospital-acquired?
A. Hospitals house large numbers of people whose
immune systems are often in a weakened state.
B. Increased use of outpatient treatment means that
patients in the hospital are more vulnerable.
C. Medical staff move from patient to patient, providing a
way for pathogens to spread.
D. Many medical procedures bypass the body's natural
protective barriers.
E. All of the above
Mechanisms of Resistance
Drug Inactivation
Antibiotic-Inactivating Enzymes
Result
R S R S CH3
CH3
N Penicillinase O C N
O COOH H COOH
OH
Outer membrane
Efflux Drug Pumps
Efflux pumps remove compounds from cell
Increased production of pumps allows
faster removal
Drug
Inactive drug Active
pump drug
pump
Cell surface
of microbe Cell surface
of microbe
Target Modification
Minor structural changes can prevent binding
For example, penicillin binding proteins (-lactam
antibiotics) and ribosomal subunit (macrolides)
Use of Alternate Metabolic Pathway
Drug inhibits
A B C D Product
X
.
C D
Question
Modified from: Spellberg et al, 2009. Trends in Antimicrobial Drug Development: Implications for the
Future, Clinical Infectious Diseases 9(38): 1279-1286.
Strategies to Limit Drug Resistance
Speed development of new antibiotics