Bacteria and antibiotics Flashcards
Gram positive vs gram negative
Outer membrane?
Gram negative
Gram positive vs gram negative
Techoic acid?
Gram positive
Gram positive vs gram negative
Capsule?
Some of both
Gram positive vs gram negative
Lipopolysaccharide (endotoxin)
Gram negative
Gram positive vs gram negative
Internal cell membrane and cell wall made of peptidoglycan?
Both
Gram positive vs gram negative
Thinner cell wall?
Gram negative
Gram positive vs gram negative
Periplasmic space?
Gram negative
Antibiotics that inhibit bacterial cell wall synthesis
B-lactam antibiotics
block the cross-linking of PG units by inhibiting the peptide bond formation reaction catalyzed by transpeptidases, which are also known as penicillin-binding proteins (PBP)
B-lactam antibiotics examples
penicillin
Cephalosporin
Carbapenems (imipenem, meropenem)
resistance to these antibiotics is mediated by bacterially synthesized B-lactamase enzymes that destroy the B-lactam ring
Clavulanic acid and sulbactam?
inhibitors of B-lactamase, thereby reducing resistance of bacterial species to the penicillins
ceftriaxone
third generation cephalosporin
more resistant to beta-lactamases than narrow spectrum penicillins
Parenteral, broad spectrum beta-lactams such as ceftriaxone are the preferred antibiotics for initial empiric therapy of pyelonephritis caused by most pathogens (e.g. E. coli, Proteus, Klebsiella).
peptidoglycan
a covalently cross-linked polymer matrix composed of peptide-linked β-(1–4)-N-acetyl hexosamine
The mechanical strength afforded by this layer of the cell wall is critical to a bacterium’s ability to survive environmental conditions that may alter prevailing osmotic pressures; of note, the degree of PG cross-linking can be correlated with the structural integrity of the cell
Maintenance of the peptidoglycan layer
Maintenance of the PG layer is accomplished by the activity of transglycosylase and transpeptidase enzymes, which add disaccharide pentapeptides to extend the glycan strands of existing PG molecules and cross-link adjacent peptide strands of immature PG units, respectively
Why treat with cell wall synthesis inhibitor
Successful treatment with a cell wall synthesis inhibitor can result in changes to cell shape and size, induce cellular stress responses, and culminate in cell lysis
classes of antibiotics that interfere with specific steps in homeostatic cell wall biosynthesis.
β-lactams and glycopeptides
MOA Beta lactams
binds to penicillin-binding proteins (PBPs). This binding inhibits transpeptidation. Crosslinked peptidoglycan chains form the bacterial cell wall.
block the cross-linking of PG units by inhibiting the peptide bond formation reaction catalyzed by transpeptidases, which are also known as penicillin-binding proteins (PBP)
This inhibition is achieved by penicilloylation of a PBP’s transpeptidase active site –- the β-lactam drug molecule (containing a cyclic amide ring) is an analog of the terminal D-alanyl-D-alanine dipeptide of PG, and acts a substrate for the enzyme during the acylation phase of cross-link formation –- which disables the enzyme due to its inability to hydrolyze the bond created with the now ring-opened drug
Glycopeptide antibiotics example
Vancomycin
Glycopeptides (vancomycin) is a large bulky molecule that can’t cross the outer membrane of gram-negative bacteria, such as E. coli.
MOA glycopeptide antibiotics
inhibit PG synthesis through binding with PG units (at the D-alanyl-D-alanine dipeptide) and by blocking transglycosylase and transpeptidase activity
generally act as steric inhibitors of PG maturation and reduce cellular mechanical strength, although some chemically-modified glycopeptides have been shown to directly interact with the transglycosylase enzyme
β-lactams vs glycopeptides
β-lactams can be used to treat Gram-positive and Gram-negative bacteria, whereas glycopeptides are effective only against Gram-positive bacteria due to low permeability
MOA Fosfomycin
Inhibit the synthesis of individual PG units
It is a structural analog of phosphoenolpyruvate, and inhibits an enzyme (enolypyruvate transferase) involved in a very early intracellular stage of cell wall synthesis. It is used for treating uncomplicated UTIs (and not pyelonephritis).
MOA Bacitracin
Inhibit the transport of individual PG units
Daptomycin?
Lipopeptide: affect structural integrity via their ability to insert into the cell membrane and induce depolarization.
not effective against gram-negative bacteria
Transglycosylase activity?
add disaccharide pentapeptides to extend the glycan strands of existing PG molecules
50S ribosome inhibitors
include the macrolide (e.g., erythromycin), lincosamide (e.g., clindamycin), streptogramin (e.g., dalfopristin/quinupristin), amphenicol (e.g., chloramphenicol) and oxazolidinone (e.g., linezolid) classes of antibiotics86, 87.
In general terms, 50S ribosome inhibitors work by physically blocking either initiation of protein translation (as is the case for oxazolidinones), or translocation of peptidyl-tRNAs, which serves to inhibit the peptidyltransferase reaction that elongates the nacent peptide chain.
