antibiotic resistance Flashcards
for an antibiotic to be effective there must be
essential target susceptible to a low concentration of the antibiotic
must penetrate the envelope and reach the target in an active form in a sufficient quantity
carbapenems
multiple modifiable groups
last resort antibiotic
b lactamases
resistance occuring in enterobacteriacae - carbapenemases
mechanisms on resistance
antibiotic inactivation permeability changes efflux alter/remove target metabolic bypass
intrinsic and aquired
resistance
intrinsic - outer membrane of gram negative bacteria - vancomycin cannot get into periplasm (1550 daltons)
acquired:
endogenous - mutation
exogenous - horizontal gene transfer of plasmids
antibiotic inactivation
b- lactamases
reduce concentration of active antibiotic
break bond in the b lactam ring - becomes penicilloic acid
use of antibiotics
adds selective pressure, will always drive resistance
Trilosan disinfectant now banned - increased resistance by inducing promoter mutations
reducing the concentration of active antibiotic in the cell - modification
aminoglycosides phosphorylation acetylation adenylation bulky residues on antibiotic, no longer interacts with RNA/ribosome
chloramphenicol is modified by acetyltransferases
permeability changes
outer membrane porins in gram negative bacteria size - less than 600 daltons
mycobacteria have mycolic acid - issue of hydrophillic antimicrobials - cannot get into cells (Isoniozid used)
pseudemonas aeruginosa resistant to Imepenem by reducing OprD porin protein expression. Coupled with cephalasporinase.
BUT porin deficient mutant less fit - nutrients cannot get in
efflux
gram negative bacteria
multiple substrates can be effluxed
ATP or anti-port (H+) driven
intrinsic or acquired
RND pumps are intrinsic in gram negatives (pump out bile acid)
RND spans periplasm (outer and inner membranes)
gram positives have efflux pump in cytoplasmic membrane, captures drug in cytoplasm or bilayer, pumps back into the environment
RND type - AcrAB-TolC complex spread cross outer and inner membrane
tripartite
TolC is porin,
AcrAB binds substrate and binds TolC
energy from antiport
multi drug resistance - penicillins, macrolides, fusidic acid
Pseudemonas and acinetobacter also have intrinsic pumps which bind multiple substrates
some inducable
alterations of target
altering concentration due to mutations in regulating genes - more target = more inhibitor required
alter affinity of drug for target by altering target
increase target concentrations
D-cycloserine resistance in Mycobacterium smegmatis
resistance by over production of target - enzyme alanine racemase
single mutation in the genes promoter region resulted in elevated gene expression
higher concentrations of antibiotic is required
target mutation
penicillin resistance by strep pneumonia
mosaicism- PBP DNA is combined with blocks of conserved sequences with blocks of variant sequences by horizontal gene transfer
reduced binding to penicillin
metabolic bypass
reliance on an alternative pathway to that inhibited
vancomycin resistance in enterococcus
metabolic bypass
expression of alternative pathway - produces D alanine D lac - reduces hydrogen bonding with vancomycin - reduced affinity by 10,000.
MRSA
associated with mobile genetic element MecA
encodes a new penicillin binding protein with decreased affinity for B lactams
still sensitive to vancomycin