Treatment of Infections
Cystic Fibrosis and the Lungs
• Issues that arise in the lungs from cystic fibrosis stem from defective CFTR
1. The defective CFTR leads to less surface airway fluid due to ion imbalances (influx of Na+ into
cell and consequently water follows). Reduction in the airway fluid leads to defective
mucocilliary action and more viscous (sticker, thicker) mucous that obstruct airway passages
and predispose patients to recurrent pulmonary infections (Staph aureus, Haemophilus
influenzae and Pseudomonas aeruginosa are the 3 most common organisms responsible for
lung infection)
2. Impaired defensin functionality – Defensins are proteins secreted by epithelial cells that lyse
microbial cells. In cystic fibrosis, the airway fluid is of abnormal salt concentration which
reduces the killing power of these proteins
3. More severe (but ineffective) inflammatory response to infective microbes. The
inflammatory response starts damaging healthy epithelia resulting in a cycle of ongoing
inflammation and damage
4. Impaired attraction of microbes to epithelial cells where they would normally be
endocytosed and the epithelial cell shed and expectorated out of lung
Antibiotics
Class
Beta Lactams
Agent
Penicillins
Cephalosporins
Carbapenem
Monobactam
Glycopeptides
Vancomycin
Aminoglycosides
Gentamicin
Streptomycin
Tobramycin
Amikacin
Tetracycline
Doxycycline
- inhibit bacterial protein synthesis by
binding to 30S ribosome, leading to incorrect
binding of tRNA resulting in false protein
Chloroamphenicol
Chloroamphenicol
Macrolides
Erythromycin
Clarithromycin
Roxirithromycin
- inhibit protein synthesis by binding to 50S
ribosome and inhibit peptidyl transferases
(responsible for peptide bond formation)
- inhibit protein synthesis by binding to 50S
ribosome that suppresses ribosome
advancement (prevents translocation)
Tetracyclines
Mechanism of Action
- Inhibit cell wall synthesis by binding to
penicillin binding proteins (PBPs) on bacterial
membrane. PBP binding leads inhibition of
transpeptidase activities required for crosslinking of peptidoglycan chains (final step in
cell wall synthesis)
- PBP binding also activates autolytic
enzymes that destroy cell wall
- inhibit cell wall synthesis by binding to
precursor molecule implicated in bacterial
cell wall synthesis and disrupts it
- inhibit protein synthesis by accumulating
intracellularly via transport system in
bacterial membrane (not in mamallian cell
membranes) and blocking tRNA binding site
on 30S ribosome
Commonly used against
- Gram positive are most
susceptible as
antiobiotic can easily
pass through cell
membrane
- Most can’t penetrate
gram negative cell
membrane
- Gram positive,
especially against MRSA
- Can’t penetrate gram
negative cell
- Gram positive and
gram negative
- Broad spectrum of
both Gram positive and
negative
- Bacteria develop
specialised pumps that
pump out drug out of
cell  Resistance
- Broad spectrum of
both Gram positive and
negative
- Gram positive and
negative
- wider spectrum than
penicillins
- commonly used as
substitute for penicillin
in allergic patients
Antimetabolites
Sulphonamides
Trimethprim
Inhibition of
Nucleic Acid
Synthesis
Quinolones
Rifampin
Metronidazole
Disruptors of Cell
Membrane
Polymyxin
- inhibit bacterial folate syntheis by inhibiting
bacterial enzyme that converts
p-aminobenzoic acid (PABA) to folic acid
- folate is necessary for nucleic acid synthesis
- Quinolones inhibit bacterial DNA gyrases
- Rifampin inhibit RNA polymerase
- Mteronidazole increase production of
cytotoxic compounds that disrupt host DNA
- Have selective effect on bacterial cell
membranes
- act as detergents disrupting phospholipid
components of membrane  increased
permeability  cell death
- Gram positive and
negative
- Quinolones for gram
negative UTI and GITI
only
- Rifampin for gram
positive cocci
- mteronidazole for
anaerobic bacteria
- gram negative
(neurotoxixity and
nephrotoxicity are major
side effects)
Antibiotic Resistance
1.


Antibiotic Inactivation
Enzymes within the microbe that cleave or modify the drug in some way
E.g. Beta-lactamases – degrade beta-lactam ring of antibiotics rendering the antibiotic
ineffective. Many different lactamases exist, with differing specificities. Thus a given betalactamase may make an organism resistant to penicillins but not cephalasporins (and viceversa)
2.


Alter Drug Target
Microbe alters the target binding regions so that the antibiotic cannot bind, or it binds very
poorly
E.g. alteration of Penicillin binding protein (PBP) site on penicillin antibiotics
3.

Alter cell wall structure so that antibiotic cannot enter
This may be a decreased entry or no entry at all
4.

Remove antibiotic from cell
Some bacteria develop resistance to antibiotics by synthesising efflux pups which remove the
antibiotic out of the cell as fast as it enters the cell
5.

Alternate Metabolic Pathway
The microbe can use alternative metabolic pathway that remains unaffected by the
antibiotic.
Drug may completely inhibit one pathway but the microbe has other mechanisms to
compensate
E.g. new folate metabolism pathway


Acquiring Resistance
• Microbes can acquire resistance to antibiotics through chromosomal mutations or from
extrachromosomal elements (plasmids)
i.
Plasmids – circular pieces of DNA that replicate independently & carry resistance genes
ii.
Mutation of chromosomal gene – spontaneous mutation of gene sequence
iii.
Conjugation – cell to cell contact  transfer of chromosomal DNA from one bacterium
to another. Usually through plasmids via sex pili of bacteria
iv.
Transduction - Process by which plasmid DNA is enclosed in a bacteriophage (virus that
infects bacteria), and transferred to another bacterium of same species.
v.
Transformation – bacteria take up DNA from environment and incorprate into genome
vi.
Transposition – DNA sequences jump from one site to another in the genome of a cell.
Eg. Plasmid to genomic DNA, DNA to plasmid or plasmid to plasmid