Molecular Basis of Bacterial Infections Evelien Floor
Antibiotic resistance
Mechanisms of resistance
There are two types of antibiotic resistance:
1. Innate resistance
Antibiotic cannot enter the cell or target is absent
2. Acquired resistance
The bacterium is normally susceptible for the antibiotic, but acquires mutations or even
novel genes
Here we talk about acquired resistance. For every antibiotic currently in use acquired resistance has
been documented. Sometimes before an antibiotic is on the market there already is resistance but
sometimes it takes 50 years to acquire resistance. It is not a question whether resistance will occur,
but when.
Antibiotics are special because the bacterium that needs to be eliminated can develop resistance.
This resistance is not only of importance for the patient you treat, but all other patients, who may
acquire this resistant bacterium. This is not an issue with other drugs; a problem for one patient does
not affect treatment of another patient.
There are different mechanisms of acquiring resistance in bacteria:
The presence of an enzyme that inactivates the antibiotic
o -lactams, aminoglycosides and macrolideslactams, aminoglycosides and macrolides
o -lactams, aminoglycosides and macrolideslactamase is such an enzyme
Modification of the antibiotic, which reduces/eliminates binding of the antibiotic to the
target
o Aminoglycosides
The presence of an alternative enzyme for that inhibited by the antibiotic
o -lactams, aminoglycosides and macrolideslactams, trimethoprim and sulfonamides
o PBP PBP2a
Mutation in the target (target site modification), which reduces binding of the antibiotic
to the target
o -lactams, aminoglycosides and macrolideslactam, fluoroquinolones, rifampin, macrolides, lincosamides, streptogramines
and ketolides
Decreased permeability (reduced uptake of the antibiotic)
o -lactams, aminoglycosides and macrolideslactams
Active efflux of the antibiotic
o -lactams, aminoglycosides and macrolideslactams, macrolides, fluoroquinolones, tetracyclines and almost all other
antibiotics
Removal by binding of the antibiotic
o Glycopeptides
o Overproduction of D-lactams, aminoglycosides and macrolidesAla-lactams, aminoglycosides and macrolidesD-lactams, aminoglycosides and macrolidesAla so there is not enough vancomycin to bind to all
the D-lactams, aminoglycosides and macrolidesAla-lactams, aminoglycosides and macrolidesD-lactams, aminoglycosides and macrolidesAla groups
Protection of the target
o Fluoroquinolones work on enzymes that wind up or unwind the DNA
In some species not all the resistance mechanisms are used. In Enterobacteriaceae (E. coli) for
instance only three of the resistance mechanisms are used: decreased permeability, efflux and
inactivation of -lactams, aminoglycosides and macrolideslactams via -lactams, aminoglycosides and macrolideslactamase.
Resistance mutations and or required genes are on:
1
Antibiotic resistance
Mechanisms of resistance
There are two types of antibiotic resistance:
1. Innate resistance
Antibiotic cannot enter the cell or target is absent
2. Acquired resistance
The bacterium is normally susceptible for the antibiotic, but acquires mutations or even
novel genes
Here we talk about acquired resistance. For every antibiotic currently in use acquired resistance has
been documented. Sometimes before an antibiotic is on the market there already is resistance but
sometimes it takes 50 years to acquire resistance. It is not a question whether resistance will occur,
but when.
Antibiotics are special because the bacterium that needs to be eliminated can develop resistance.
This resistance is not only of importance for the patient you treat, but all other patients, who may
acquire this resistant bacterium. This is not an issue with other drugs; a problem for one patient does
not affect treatment of another patient.
There are different mechanisms of acquiring resistance in bacteria:
The presence of an enzyme that inactivates the antibiotic
o -lactams, aminoglycosides and macrolideslactams, aminoglycosides and macrolides
o -lactams, aminoglycosides and macrolideslactamase is such an enzyme
Modification of the antibiotic, which reduces/eliminates binding of the antibiotic to the
target
o Aminoglycosides
The presence of an alternative enzyme for that inhibited by the antibiotic
o -lactams, aminoglycosides and macrolideslactams, trimethoprim and sulfonamides
o PBP PBP2a
Mutation in the target (target site modification), which reduces binding of the antibiotic
to the target
o -lactams, aminoglycosides and macrolideslactam, fluoroquinolones, rifampin, macrolides, lincosamides, streptogramines
and ketolides
Decreased permeability (reduced uptake of the antibiotic)
o -lactams, aminoglycosides and macrolideslactams
Active efflux of the antibiotic
o -lactams, aminoglycosides and macrolideslactams, macrolides, fluoroquinolones, tetracyclines and almost all other
antibiotics
Removal by binding of the antibiotic
o Glycopeptides
o Overproduction of D-lactams, aminoglycosides and macrolidesAla-lactams, aminoglycosides and macrolidesD-lactams, aminoglycosides and macrolidesAla so there is not enough vancomycin to bind to all
the D-lactams, aminoglycosides and macrolidesAla-lactams, aminoglycosides and macrolidesD-lactams, aminoglycosides and macrolidesAla groups
Protection of the target
o Fluoroquinolones work on enzymes that wind up or unwind the DNA
In some species not all the resistance mechanisms are used. In Enterobacteriaceae (E. coli) for
instance only three of the resistance mechanisms are used: decreased permeability, efflux and
inactivation of -lactams, aminoglycosides and macrolideslactams via -lactams, aminoglycosides and macrolideslactamase.
Resistance mutations and or required genes are on:
1
