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Bacterial resistance to antibiotics

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rasha eltamany

on 4 January 2013

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Transcript of Bacterial resistance to antibiotics

Bacterial resistance to antibiotics Antibiotic inactivation by hydrolysis
Many antibiotics have hydrolytically susceptible chemical bonds
Several enzymes destroy antibiotic activity by cleaving these bonds
These enzymes excretedby the bacteria
e.g. lactamases cleave the b-lactam ring 1.Antibiotic inactivation biochemcical aspects biology of antibiotic resistance genetic aspects 1-antibiotic inactivation
group transfer
redox process 2-Target modification
1.Peptidoglycan structure alteration
2.Protein synthesis interference
3.DNA synthesis interference 3.Efflux pumps and outer membrane (OM)
permeability 4-Target bypass Mutations
spontaneous mutation
adaptive mutagenesis horizontal gene transfer
(conjogative) transposons
integrons Antibiotic inactivation by group transfer
(transferases) these enzymes inactivate antibiotics (aminoglycosides, chloramphenicol, streptogramin, macrolides or rifampicin) by chemical substitution
adenylyl, phosphoryl or acetyl groups are added to the periphery of the antibiotic molecule. Antibiotic inactivation by redox process
oxidation or reduction of antibiotics by pathogenic bacteria.
e.g. oxidation of tetracycline antibiotics by the TetX enzyme 2.Target modification 1.Peptidoglycan structure alteration
The peptidoglycan component of cell wall
excellent selective target for the antibiotics
altering the target protein to which the antibacterial agent binds >>>> by modifying or eliminating the binding site results in antibacterial resistance.
e.g., change in penicillin-binding protein 2b in pneumococci, which results in penicillin resistance. 2.Protein synthesis interference
A wide range of antibiotics interfere with protein synthesis
The resistance to antibiotics that interfere with protein synthesis is achieved by modification of the specific target.
The macrolide, lincosamide and streptogramin B group of antibiotics block protein synthesis in bacteria by binding to the 50S ribosomal subunit
Resistance to these antibiotics is results from a post-transcriptional modification of the 23S rRNA component of the 50S ribosomal subunit. 3.DNA synthesis interference
Fluoroquinolones interact with the DNA gyrase and topoisomerase IV enzymes and prevent DNA replication and transcription.
Resistance is conferred by mutations in specific regions of the structural genes that sufficiently alter these enzymes preventing the binding of antibiotics . Conjugation transduction transformation By :Rasha El tamany Acquired intrinsic adaptive Resistance Horizonta transfer mutation The efflux pumps
export the antibiotics out of the cell
Efflux pumps affect all classes of antibiotics, especially the macrolides, tetracyclines, and fluoroquinolones

Outer membrane (OM) permeability
(OM) permeability results in reduced antibiotic uptake
Gram-negative bacteria possess an outer membrane consisting of an inner layer containing phospholipids and an outer layer containing the lipid A moiety of lipopolysaccharides (LPS).
This composition of the outer membrane (OM) slows down drug penetration. 4.Alteration of metabolic pathway (Target bypass)

some sulfonamide-resistant bacteria do not require para-aminobenzoic acid (PABA), an important precursor for the synthesis of folic acid and nucleic acids in bacteria inhibited by sulfonamides, instead, like mammalian cells, they turn to using preformed folic acid. a. Reduced Permeability or Uptake
Neisseria gonorrhoea porin can acquire mutations that can cause resistance to penicillin and tetracycline

b. Increased Efflux Activity
Tetracycline efflux ...Under normal conditions, the efflux gene, TetK, is not expressed, due to a suppressor that is bound to the promoter region. However, in the presence of Tetracycline, it binds to the repressor, relieves the suppression, and causes transcription and translation of the efflux pump, thereby leading to Tetracycline resistance. c. Enzymatic Inactivation
Beta-lactamases, which can cleave beta-lactam antibiotics and cause resistance.
A second example is the Aminoglycoside-inactivating enzymes, which can add Acetyl, Adenyl, and Phosphoryl groups to inactivate the antibiotic.

d. Alteration of Drug Target
penicillin resistance, which is due to alterations in penicillin binding proteins
vancomycin prevents cross-linking of peptidoglycan by binding to D-Ala-D-Ala dipeptide of the muramyl peptide. Most G+ bacteria acquire vancomycin resistance by changing D-Ala-D-Ala to DAla-D-lactate, which does not bind to vancomycin. e. Loss of Enzymes in Drug Activation
new mechanism of drug resistance.
the antibiotic itself is a prodrug, which has no direct activity against the bacteria. Rather, it relies on the activation by a bacterial enzyme.
Metronidazole (MTZ) prodrug. MTZ is activated through RdxA (nitroreductase), and then forms reactive species that damage the DNA.
Thus, mutations in this enzyme cause resistance to Metronidazole. Type of resistance intrinsic acquired adaptive Aquisition not acquired , part of the genetic make-up of the strain or species. mutation
horizontal transfer changes in gene expression triggered by enviromental factors or presence of antimicrobial characteristic inheritable
independent on enviroment inheritable
independent on enviroment not inheritable
generaly revert upon removal of inducing signal
dependent on enviroment Examples of Chromosomal Mutations: 3.Efflux pumps and outer membrane (OM) permeability Thank you
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