1.14. Antibiotic action & mechanisms of bacterial resistance Flashcards
list the mechanisms of action of antibiotic agents
- inhibit cell wall synthesis
- disrupt cell membrane
- inhibit protein synthesis
- inhibit DNA
which antibiotic agents inhibit cell wall synthesis?
- B-lactams
- glycopeptides
- Fosfomycin
which antibiotic agents disrupt the cell membrane?
- Lipopeptides
2. Polypeptides
what do antibiotic agents act on to inhibit protein synthesis?
- inhibit 30s ribosome (AT)
2. inhibit 50s ribosome (mol)
which antibiotic agents inhibit DNA?
- Quinolones (inhibit DNA replication)
- Rifamycins (inhibit DNA transcription)
- Metronidazole (inhibit DNA function)
- Sulphonamides & trimethoprim (inhibit DNA synthesis)
(1) β-lactams
•β-lactam antibiotics contain a β-lactam ring in their molecular structures •Work by inhibiting peptidoglycan cross-linkage •Include: 1. Penicillins 2. β-lactam-inhibitor combinations 3. Cephalosporins 4. Monobactams 5. Carbapenems
(2) Glycopeptides
- Inhibit peptidoglycan cross-linking in gram positive organisms
- E.g. vancomycin, teicoplanin
(3) Fosfomycin
•Inhibits the enzyme pyruvyl transferase during the first step of peptidoglycan synthesis
(1) Lipopeptides
- Binds irreversibly to the cytoplasm membrane of bacteria resulting in disruption of cellular ion concentration gradients. This causes cell death.
- Activity against Gram positive bacteria E.g. Daptomycin
2)Polypeptides
•Disrupts the lipid component of the outer membrane of gram negative bacteria leading to cell death.
E.g. polymixinB , polymixinE (colistin)
Inhibit 30S ribosome
Act on 30S ribosomal subunit. Prevent translation of mRNA to tRNAfor peptide chain synthesis
•1) Aminoglycosides
•E.g. streptomycin, gentamycin, amikacin, tobramycin
2) Tetracyclines
•E.g. doxycycline, minocycline
Inhibit 50S ribosome
Act by binding to 50S ribosomal subunit thereby interfering with protein chain synthesis
1)Macrolides
E.g erythromycin, clarithromycin, azithromycin
2) Lincosamides
E.g. clindamycin
3) Oxazolidones
E.g. Linezolid
(1) Inhibit DNA replication
- Quinolones
- Inhibit bacterial DNA gyrase & Topoisemeraserequired for DNA uncoiling leading to inhibition of DNA replication and eventually cell death
- Narrow spectrum/first generation=Nalidixicacid
- Broad spectrum /second generation= Ciprofloxacin, levofloxacin, ofloxacin, •Expanded spectrum / third generation=Sparfloxacin
- Extended spectrum /fourth generation=Gatifloxacin, moxifloxacin
(2) Inhibit DNA transcription
•Rifamycins
•Acts by binding to bacterial DNA-dependant RNA polymerase, resulting in inhibition of RNA synthesis.
E.g. rifampicin
(3)Inhibit DNA function
Metronidazole
•Receives electrons under anaerobic conditions and forms toxic metabolites that damage bacterial DNA
(4)Inhibit DNA synthesis
Sulphonamides and trimethoprim
•Act by inhibiting the synthesis of tetrahydrofolate which is necessary for bacterial DNA synthesis
Intrinsic resistance
- Innate ability of a bacterial species to resist the activity of a particular antimicrobial agent
- The organism possesses inherited structural or functional characteristics
- This kind of resistance is predictable
Acquired resistance
- Changes in usual genetic makeup of a microorganism
* The resistance is unpredictable
list the mechanisms of acquiring resistance genes in bacteria
- transformation
- conjugation
- transduction
Transformation
- Bacteria acquire new genetic material from the environment
- Resulting in an altered gene with altered affinity for antibiotic
- E.g. Streptococcus pneumoniae can acquire short fragments of penicillin-binding protein (PBP) genes from closely related species to form a new PBP that has less affinity for penicillin and therefore resistance develops
Conjugation
- Bacteria contain plasmids which are circular DNA structures that are found in the cytoplasm
- Genes carried by plasmids include those that code for metabolic enzymes, virulence and antibiotic resistance
- Plasmids can pass from one bacterium to another, through pili, allowing resistance genes to spread
- Requires cell-to-cell contact
- E.g. Enterobacteriacea & resistance to β-lactams-extended spectrum β-lactamases are found on plasmids
Transduction
- Transfer of DNA from one bacterium into another via bacteriophages (a virus that infects bacteria)
- When a bacteriophage infects a bacterium, it takes over the bacteria’s genetic processes to produce more phage.
- Bacterial DNA may be incorporated into the new phage DNA during this process .
- Once the bacteria dies these new phage go on to infect other bacteria with genes from the previously infected bacterium
list the mechanisms of antibiotic resistance
- enzymatic inactivation or alteration
- reduced availability of antibiotic
- modification of the antibiotic target site
Enzyme inactivation
•Enzymes bind to antibiotic molecule & either destroy antibiotic molecule or prevent it from binding to target sites.
•Example:
•β-lactamases produced by some bacteria cleave β-lactam ring of β -lactam antibiotics which results in inactivation of the antibiotic
(Staphylococcus aureus, Neisseria gonorrhoea, Haemophilus influenzae)
Enzyme modifying the antibiotic:
some bacteria produce enzymes that add an inactivating chemical group to the antibiotic causing the antibiotic to be inactivated •Example
•acetyl, phospho & adenylyl tranferasescan modify the aminoglycoside antibiotic in Gram positive & Gram negative bacteria resulting in poorer affinity of the antibiotic to ribosomes
(Staphylococcus aureus, Pseudomonas spp)
name 3 mechanisms which lead to reduced availability of antibiotic
- impermeability
- porin loss
- efflux pumps
(1) Impermeability
bacteria are intrinsically resistant to antibiotic due to being impermeable to that antibiotic
•Example: Pseudomonas spp & β-lactams ( Penicillin G, aminopenicillins & aminopenicillin –β-lactamase inhibitor combinations ,first, second & third generation cephalosporins, ertapenem) –(small porinsthat do not allow these agents to permeate)
•Aminoglycosides enter bacteria by an oxygen dependent transport mechanism and therefore have little effect against anaerobic bacteria
(2) Porin loss
•Example: Escherichia coli & βlactams(Not intrinsically resistant to beta lactam agents however, porin loss can occur conferring the resistance.)
(3)Efflux pumps
•Antibiotics pumped out of cell
so rapidly that they cannot accumulate in the cytoplasm
•Example:Escherichia coli and streptococci resistance to macrolides, tetracyclines, quinolones
3) Modification of the antibiotic target site
•Antibiotics normally bind to specific binding proteins on the bacterial cell surface. •Changed site= blocked binding
Examples
•Ribosomal point mutation: tetracyclines, macrolides, clindamycin, aminoglycosides
•Altered DNA gyrase: Quinolones
•Modified penicillin binding proteins: Penicillins
•Mutation in DNA dependant RNA polymerase: Rifampicin
