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Lecture 4

MICB 201 Lecture Notes - Lecture 4: Polymyxin, Lactam, Autolysin

14 pages45 viewsFall 2017

Department
Microbiology
Course Code
MICB 201
Professor
Dave Oliver
Lecture
4

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Origin of ABs
Archaea don’t cause illnesses in humans information we have regarding
antibiotics only applies to bacteria
Deaths from infectious diseases has dramatically declined since 1900 b/c
improved sanitation, sewage treatment, medical care, decrease in poverty +
introduction of antibiotics
However, antibiotic-resistant bacteria spring up v fast after new AB
development
75% ABs today = naturally synthesized by soil microbes (esp. Members of
mycelial Actinobacteria)
Why do some bacteria synthesize ABs? reason unclear,
assumed to be for biological warfare but ABs only effective at
high concentrations unlikely to be reached in natural
environments
Semi-synthetic = natural ABs modified chemically, eg. β-lactam ABs
derived from penicillin
At clinically-relevant (high) concentrations, antibiotics work by:
disrupting cellular process/structure unique to target organism, or
Disrupting cellular process/structure in targets without affecting same
process in self
Eg. interfering w/ PG synthesis, translation, transcription,
replication + membrane damage
New PG synthesis and Effects of some ABs, eg. β-lactam
Bacterial cell must double all components in order to divide, including PG
Diff modes of cell division (specifically creation of new PG) for diff
bacteria eg. for unicellular Gm +ve bacteria:
Cocci
Division synthesis
New PG synthesized on either side of cell division
site
junction/ridge btwn new + old PG = wall band
Non-
spherical
Division + elongation synthesis
new PG added on either side of cell division site
new PG additionally synthesized at sites around
cell body (but not at ends), or only at ends
New PG added by breaking bonds in preexisting PG (by autolysins) then
adding disaccharide-peptide units to existing PG
Autolysins (periplasmic enzymes) catalyze breakage of
O-glycosidic bonds btwn NAM + NAG sugars, producing free end
to add new PG
Disaccharide-peptide unit = NAM-NAG disaccharide w/
pentapeptide
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Made in cytoplasm/cytoplasmic membrane + transported
to periplasm
In periplasm, enzymes catalyze transglycosylation rxn
(O-glycosidic bond formation btwn NAM + NAG) and
transpeptidation rxn (peptide bond formation which leads
to release of 1 aa tetrapeptide)
Most clinically important ABs = β-lactams inhibit PG synthesis by binding to
enzyme that catalyzes transpeptidation, preventing transpeptidation rxn from
occurring
Many diff classes, eg. penicillins (penams), cephalosporins +
carbapenems, but all have same fxn and possess β-lactam ring
Vancomycin = inhibits PG synthesis by binding to AA4 and AA5 of pentapeptide
(if both are D-Ala), preventing both transpeptidation + transglycosylation
reactions
Can’t be used for Gm -ve b/c OM; diffuses v slowly across OM +
excluded by all porin channels
Polymyxin = one of few ABs which directly disrupts cellular structure (OM)
instead of inhibiting cellular process (eg. transpeptidation rxn)
Has polycationic ring (Full of NH3
+’s) interacts w/ negatively-charged
LPS core, displacing the Ca2+/Mg2+ ions and breaking down OM
After OM breakdown, polymyxin disrupts inner membrane by inserting its
hydrocarbon tail into membrane (detergent-like mechanism)
Only effective against Gm -ve for some reason
Chemical characteristics of ABs + Barriers to AB penetration
ABs = medium-sized chemicals (~100-1000 Daltons) in same category as
aas, nucleotides, sugars
Diff ABs = diff solubilities hydrophilic = chemicals v soluble in water,
hydrophobic = v not soluble in water
Correlated w/ relative amounts of polar/nonpolar content +
presence of charged groups
However, all ABs = high polar content + most are charged
Only the CM + OM are significant barriers to AB penetration capsular matrix,
S-layer pores + PG meshwork gaps = easy for ABs to pass thru
Although most ABs = v polar + charged, many are somehow able to
diffuse across CM freely
Some are passively/actively transported by CM permeases if
structurally similar to normal substrate, eg. Streptomycin
OM = less fluid + better barrier than CM, but allows ABs w/ high nonpolar
content to diffuse (eg. erythromycin + rifampin)
Some are transported into periplasm by porins β-lactams b/c
structurally similar to aa
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Zwitterionic penams (eg. ampicillin + amoxicillin) penetrate
porins faster than anionic penams more effective ABs
Self-promoted uptake: some ABs “cross” OM by disrupting
structure, eg. polymyxin + streptomycin
An AB doesn’t either diffuse thru bilayer or travel thru porins; some can
take both routes depending on pH (affects ionization)
Factors contributing to a bacteria’s resistance to ABs:
Factor
How it helps with resistance
How to acquire
Can
antibiotic
pass thru
barriers?
Gm -ve or
Gm +ve
OM issues
Gm -ve generally more resistant
b/c OM; some ABs diffuse so slowly
basically useless
in Gm -ve, also consider ratio
of LPS vs. PL in OM, amount of
porin channels + size/selectivity
of porin channels
Can
antibiotic
bind?
Presence
+ suitability of
target sites
Bacteria will be resistant to ABs if
they lack the target sites of the ABs
eg. Mycoplasma sp. = no PG, so
resistant against β-lactam ABs
Vancomycin needs D-Ala @
AA4 + AA5
β-lactam ABs target
transpeptidase enzymes, but since
diff bacteria synthesize
transpeptidase enzymes w/ slightly
diff structures, variations exist btwn
bacterial resistance
Alteration to
target so AB can’t
bind
or replacement
with a different, but
functionally
equivalent,
molecule that AB
can’t bind to
Antibiotic-
modifying
enzymes
present?
Some bacteria can chemically
modify + inactivate ABs w/
enzymes
β-lactamases/Bla proteins
catalyze hydrolysis of β-lactam
rings
Chloroamphenicol transcetylase
(Cat) catalyzes acetylation of
chloramphenicol
Acquisition of
enzyme which
chemically modifies
+ deactivates AB
Antibiotic
efflux and/or
decreased
influx
Some bacteria have efflux protein
which transports AB out of cell
when it enters (specificity varies
btwn organisms)
Change in cell
envelope
composition that
decreases AB influx
Acquire new
efflux protein
Basically, acquired AB resistance (phenotype changes) comes from mutation
of existing genes or addition of new genes (genotype changes).
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