Classes of antibiotics
(BFMATS) Beta lactams Fluoroquinolones Macrolides Aminoglycosides Tetracylines Sulfonamides
Beta Lactams
Inhibit cell wall synthesis (bacteriocidal) 4 types: - Penicillins - Cephalosporins - Carbapenems - Monobactams
Eg. Penilcilin G, Amoxicilin, Flucoxacilin
Fluoroquinolones
Inhibit DNA synthesis (bacteriocidal)
Eg. Norflaxacin
Ciproflaxacin
Macrolides
Inhibit protein synthesis, target 50S subunit (bacteriostatic)
Eg. Erythromycin
Aminoglycosides
Inhibit protein synthesis
target 30S subunit
Eg. gentamicin, streptomycin
Tetracylines
Inhibit protein synthesis
target the 30S subunit
Sulfonamides
Block bacterial cell metabolism by inhibiting enzymes
Beta lactams mechanism
- Gram positive and gram negative bacteria have peptidoglycan
- The peptidoglycan layer is made from alternating NAG (N-acetyl glucosamine) and NAM (N-acetyl muramic acid) and amino acid cross links
- The transpeptidase enzyme (penicillin binding protein) is involved in cross linking
- B- lactams contain a B-lactam ring that is able to bind to the enzymes that cross link peptidoglycans
- They interfere by binding to transpeptidase, preventing bacterial cell wall synthesis
- Gram positive bacteria have a high internal osmotic pressure, without a firm cell wall they burst
- The antibiotic + penicillin binding protein complex stimulate the release of autolysins that are able to digest the existing cell wall
B- lactam resistance
- Enzymatic inactivation
- Bacteria synthesise a B-lactamase, an enzyme that attacks the B-lactam ring
- It is most commonly produced by gram negative bacteria
Macrolide resistance
- Post transcriptional mutation of the 23S rRNA
- Drug inactivating esterases
- Efflux pumps
Tetracyline resistance
- Enzymatic inactivation of tetracyline
- Efflux pumps (encoded on plasmid)
- Stop protein binding to tetracyline
Fluoroquinolone resistance
- Produce proteins that bind to DNA gyrase, protecting it from quinolones
- Efflux pumps
Aminoglycoside resistance
- Decreased cell permeability
- Altering ribosomal binding site
- Aminoglycoside modifying enzyme
Antibiotics that inhibit cell wall synthesis
- Beta lactams
Antibiotics that inhibit nucleic acid synthesis
Inhibit DNA gyrase/ toiposomerase IV: quinolones
Antibiotics that inhibit protein synthesis
Inhibit 50S subunit:
- macrolides
Inhibit 30S subunit:
- aminoglycosides
- tetracylines
Mechanism of antibiotic resistance
PEDA
- Pumps (efflux)
- Enzymatic inactivation
- Decreased permeability
- Altered target site
Why are some penicillins not effective against gram negative bacteria
- Penicilins act on the peptidoglycan layer
- Gram negative bacteria have a thin peptidoglycan layer
- They have a second cell membrane outside the peptidoglycan layer so it’s harder for the penicillin to reach
How are resistant genes carried in bacteria
On the plasmid
Antibiotic resistance
1. Efflux pumps
Present in both gram +ve and gram -ve bacteria, on the inner membrane
Active transporters
They are classified based on their amino acid sequence:
All are present in gram +ve and gram -ve bacteria except the RND family
- The major facilitator superfamily (MFS)
- ATP binding cassette superfamily (ABC)
- Small multi drug resistant family (SMR)
- Resistance nodulation cell division superfamily (RND), gram -ve bacteria
- The multi antimicrobial extrusion protein family (MATE)
Efflux pumps are multifunctional tools. In E.coli they are responsible for the secretion of hemolysin which is a toxin
Antibiotic resistance
2. Enzymatic inactivation
Eg. Beta lactamases
They inactivate the B-lactam ring so the B-lactam can’t bind to the transpeptidase
Antibiotic resistance
3. Decreased permeability
By decreasing permability of the drugs across the cell surface
Antibiotic resistance
4. Altered target site
Change the structure of the protein
Eg. Modifying the penicillin binding protein (peptidase) so that antibiotics can no longer bind to the PBP and prevent its action. In MRSA, bacteria are resistant to methicillin because the protein that methicillin bind to is modified in the bacteria
Another protective mechanism found among bacteria is ribosomal protection proteins. These proteins protect the bacterial cell from antibiotics that target the cell’s ribosome to inhibit protein synthesis. This mechanism involves the binding of ribosomal protection proteins to the ribosomes of the bacterial cell, which changes its conformational shape. This allows the ribosomes to continue synthesizing proteins essential to the cell while preventing antibiotics from binding to the ribosome to inhibit protein synthesis
Antibiotic resistance
Modifying the drug by enzymes
Eg. Streptomycin can be inactivated by:
- Phosphorylation
The gene that confers resistance: APH
- Chromosomally acquired streptomycin resistance is due to mutations encoding for the ribosomal protein S12, rpsl (altered target site)
Eg. Chloramphenicol: protein synthesis inhibitor, target the 50S subunit
- Modify the drug by acetylation
- Chromosomally encoded cmlA produces more OmpA leading to reduced permeability of the bacterial cell membrane
