INFECTIOUS DISEASE PATHOLOGY

Prepared and presented by

Marc Imhotep Cray, M.D.

Scanning electron micrograph of Staphylococcus aureus bound to the surface of a human neutrophil. “Granulocytic Phagocytes,” by Frank R. DeLeo and William M. Nauseef.
 Companion Notes
 Antimicrobial Drugs and Vaccines (Rapid Review)

Marc Imhotep Cray, M.D.

 Key Concepts
 Antibiotics exploit differences between prokaryotic and
eukaryotic cells to promote specificity and limit toxicity
 For example, bacterial enzymes involved in DNA replication
and RNA synthesis are different from those found in
eukaryotic cells
 bacterial ribosome is also significantly different, allowing
selective targeting

 One of major differences between bacteria and eukaryotic cells

is peptidoglycan-containing bacterial cell wall whose synthesis
is inhibited by several antibiotics
Marc Imhotep Cray, M.D.
 Antibiotics target bacteria by five major
mechanisms
1. Inhibition of cell wall synthesis
2. Inhibition of protein synthesis
3. Inhibition of nucleic acids
4. Alterations of cellular membranes
5. Antimetabolites

Marc Imhotep Cray, M.D.

 Mechanisms of antibiotic action
A: Schematic showing cell wall–active, membrane-active, & cytoplasm-active antimicrobial agents.
B: Antibiotics that inhibit protein synthesis by interacting with different ribosome subunits.
C: Antibiotics that inhibit nucleic acid synthesis.

Somers KD and Morse SA. Lange Flash Cards: Microbiology & Infectious Diseases. New York: McGraw-Hill, 2010
Marc Imhotep Cray, M.D.
 1. Inhibition of cell wall synthesis
β-lactam antibiotics such as penicillin and cephalosporins
target peptidoglycan cross-linking by binding to and inhibiting
the action of transpeptidase enzymes
 Vancomycin inhibits cross-linking by binding terminal D-
alanine- D-alanine precursor and preventing transpeptidation
Cycloserine inhibits formation of D-alanine-D-alanine linkage
Bacitracin inhibits transport of new peptidoglycan precursors
through cell membrane
 Isoniazid and ethionamide inhibit mycolic acid synthesis in
mycobacteria

Marc Imhotep Cray, M.D.

 2. Inhibition of protein synthesis
Aminoglycosides such as streptomycin, neomycin, and
kanamycin irreversibly bind and inhibit the function of 30S
ribosomal subunits

Tetracycline reversibly inhibits binding of aminoacyl-tRNA to

30S subunit

Macrolides such as erythromycin, azithromycin, and

clarithromycin attach to a 23S RNA on 50S subunit

Chloramphenicol blocks attachment of amino acids to nascent

peptide chain on 50S subunit
Marc Imhotep Cray, M.D.
 3.Inhibition of nucleic acids
 Quinolones and fluoroquinolones such as ciprofloxacin inhibit
DNA synthesis by blocking DNA gyrase

 Rifampin binds strongly to DNA-dependent RNA polymerase

and thus inhibits RNA synthesis

 Metronidazole interacts with DNA, altering its helical structure

and causing DNA fragmentation

Marc Imhotep Cray, M.D.

 4. Alterations of cellular membranes
 Polymyxin targets cell membranes rich in phosphatidylethanolamine,
causing an increase in cellular permeability

5. Antimetabolites
 Sulfonamides and trimethoprim inhibit folic acid metabolism

Marc Imhotep Cray, M.D.

 Antibiotic Resistance Mechanisms
Bacteria have evolved a number of mechanisms to protect
themselves from action of antibiotics

Often genes encoding antibiotic resistance are carried on

transposons and plasmids, and are therefore easily
transferred from one organism to another, creating bacteria
resistant to multiple antibiotics

Marc Imhotep Cray, M.D.

 Four major mechanisms are involved
1. Inactivation of e antibiotic through hydrolysis
 An example is β-lactamases that cleave β-lactam ring of
penicillins and cephalosporins

2. Chemical modification of antibiotic through acetylation,

phosphorylation, or adenylylation
 An example is chloramphenicol acetyl transferase that transfers
an acetyl group from acetyl CoA to chloramphenicol, resulting in
its inactivation

Marc Imhotep Cray, M.D.

 Four major Ab resistance mechanisms cont.
3. Alteration of antibiotic targets through mutation
 An example is alteration of a single amino acid in ribosomal
protein S12 prevents streptomycin binding to 30S ribosome
subunit without affecting protein synthesis

4. Alterations that affect permeability (ie, decrease

intracellular concentration of antibiotic) are used by a variety of
antibiotics
 This can involve a decreased influx or an increased efflux from
bacterial cell

Marc Imhotep Cray, M.D.

 Whalen K. Ed. Lippincott Illustrated Reviews-Pharmacology, 6 Ed. 2015
Marc Imhotep Cray, M.D.
THE END

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 Further study:
eLearning (IVMS Cloud)
 Antimicrobial Drugs and Vaccines eNotes
 Infectious Disease
 Microbial biology & Immune System
 Rural Medicine Global Health (Focus on Ethiopia)

Textbooks:
 Ryan KJ and Ray CG Eds. Sherris Medical Microbiology, 5th Ed. New York: McGraw-Hill, 2010
 Carroll KC etal. Jawetz, Melnick, & Adelberg’s Medical Microbiology 27th Ed. New York:
McGraw-Hill, 2016

Marc Imhotep Cray, M.D. 15