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Many of today’s antibacterial drugs work by interfering with the growth of cell walls.
Penicillin
- Inhibits Peptidoglycan formation
- Binds to inhibits enzymes (Transpeptidases) that cross-link the peptide chains. This results in defective cell wall; Cell collapses -> lysis due to osmotic shock.
- Active against “Gram positive” bacteria only
- However, penicillin does not affect a cell wall that is already formed!
(see attachment 1)
Mechanisms of action
All beta-lactam antibiotics interfere with the synthesis of the bacterial cell wall peptidoglycan. After attachment to penicillin-binding proteins on bacteria (there may be seven or more types in different organisms), they inhibit the transpeptidation enzyme that cross-links the peptide chains attached to the backbone of the peptidoglycan.
The final bactericidal event is the inactivation of an inhibitor of autolytic enzymes in the cell wall, leading to lysis of the bacterium. Some organisms, referred to as 'tolerant', have defective autolytic enzymes and are inhibited but not lysed in the presence of the drug. Resistance to penicillin may result from a number of different causes.
Unwanted effects
Penicillins are relatively free from direct toxic effects (other than their proconvulsant effect when given intrathecally). The main unwanted effects are hypersensitivity reactions caused by the degradation products of penicillin, which combine with host protein and become antigenic. Skin rashes and fever are common; a delayed type of serum sickness occurs infrequently. Much more serious is acute anaphylactic shock, which although fortunately very rare, may in some cases be fatal. When given orally, penicillins, particularly the broad-spectrum type, alter the bacterial flora in the gut. This can be associated with gastrointestinal disturbances and in some cases with suprainfection by other, penicillin-insensitive, micro-organisms.
Streptomycin aka AMINOGLYCOSIDES: The aminoglycosides are a group of antibiotics of complex chemical structure, resembling each other in antimicrobial activity, pharmacokinetic characteristics and toxicity. The main agents are gentamicin, streptomycin, amikacin, tobramycin, netilmicin and neomycin.
Mechanism of action
Aminoglycosides inhibit bacterial protein synthesis. Their penetration through the cell membrane of the bacterium depends partly on oxygen-dependent active transport by a polyamine carrier system, and they have minimal action against anaerobic organisms. Chloramphenicol blocks this transport system. The effect of the aminoglycosides is bactericidal and is enhanced by agents that interfere with cell wall synthesis.
In paraticular, streptomycin is a protein synthesis inhibitor. It binds to the S12 Protein of the 30S subunit of the bacterial ribosome, interfering with the binding of formyl-methionyl-tRNA to the 30S subunit. This prevents initiation of protein synthesis and leads to death of microbial cells. Humans have structurally different ribosomes from bacteria, thereby allowing the selectivity of this antibiotic for bacteria. However at low concentrations Streptomycin only inhibits growth of the bacteria by inducing prokaryotic ribosomes to misread mRNA. Streptomycin is an antibiotic that inhibits both gram positive and gram negative bacteria, and is a therefore a useful broad spectrum antibiotic.
Resistance
Resistance to aminoglycosides is becoming a problem. It occurs through several different mechanisms, the most important being inactivation by microbial enzymes, of which nine or more are known. Amikacin was purposefully designed as a poor substrate for these enzymes, but some organisms have developed enzymes that inactivate this agent as well. Resistance as a result of failure of penetration can be largely overcome by the concomitant use of penicillin and/or vancomycin.
Antibacterial spectrum
The aminoglycosides are effective against many aerobic Gram-negative and some Gram-positive organisms. They are most widely used against Gram-negative enteric organisms and in sepsis. They may be given together with a penicillin in streptococcocal infections caused by Listeria sp. and P. aeruginosa. Gentamicin is the aminoglycoside most commonly used, although tobramycin is the preferred member of this group for P. aeruginosa infections. Amikacin has the widest antimicrobial spectrum and, along with netilmicin, can be effective in infections with organisms resistant to gentamicin and tobramycin.
Pharmacokinetic aspects
The aminoglycosides are polycations and therefore highly polar. They are not absorbed from the gastrointestinal tract and are usually given intramuscularly or intravenously. They cross the placenta but do not cross the blood-brain barrier, penetrate into the vitreous humour of the eye or into most other secretions or body fluids, although high concentrations can be attained in joint and pleural fluids. The plasma half-life is 2-3 hours. Elimination is virtually entirely by glomerular filtration in the kidney, 50-60% of a dose being excreted unchanged within 24 hours. If renal function is impaired, accumulation occurs rapidly, with a resultant increase in those toxic effects (such as ototoxicity and nephrotoxicity; see below) that are dose-related.
Unwanted effects
Serious, dose-related toxic effects, which may increase as treatment proceeds, can occur with the aminoglycosides, the main hazards being ototoxicity and nephrotoxicity.
Azidothymidine (AZT) AKA Zidovudine
Zidovudine is an analogue of thymidine (so it acts as a fake thymine, basically). Hence, it is a reverse transcriptase inhibitors (the enzyme responsible for making DNA from RNA). Reverse transcription is necessary for production of the viral double-stranded DNA, which is subsequently integrated into the genetic material of the infected cell (where it is called a provirus).
It can prolong life in HIV-infected individuals and diminish HIV-associated dementia. Given to the parturient mother and then to the newborn infant, it can reduce mother-to-baby transmission by more than 20%. It is generally administered orally twice daily but can also be given by intravenous infusion. The bioavailability is 60-80%, and the peak plasma concentration occurs at 30 minutes. Its half-life is 1 hour, and the intracellular half-life of the active trisphosphate is 3 hours. The concentration in cerebrospinal fluid (CSF) is 65% of the plasma level. Most of the drug is metabolised to the inactive glucuronide in the liver, only 20% of the active form being excreted in the urine.
Bio_man 8)
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