Principles of antimicrobial action

Principles of Antimicrobial Action

🍔 Antibiotics:
Substances produced by some microorganisms (or by pharmaceutical
chemists) that kills or inhibits the growth of other microorganisms.

🍔Bacteriostatic antibiotic:
An antimicrobial drug that inhibits microbial growth but
requires host defence mechanisms to eradicate the infection.
• It does not kill bacteria.
         o For example
                  chloramphenicol,
                 tetracycline and
                erythromycin.
o They stop bacterial growth and allow the host’s immune factors to ultimately clear the
infection.
• Bacteriocidal antibiotic: An antimicrobial drug that can eradicate an infection in the
absence of host defence mechanisms.
• It kills bacteria.
          o For example
penicillin,
cephalosporin, and most aminoglycosides cause microbial
death by lysis.
• They rely less on host immunity for clearing of bacterial infections.
• Synergistic effect: The summing of the simultaneous effects of two or more drugs such
that the combined effect is greater than the effect of either of the drugs when they are
given alone.
              o When two bactericidal antibiotics are used in combination, one of the two drugs must
show at least four-fold increase in antibacterial activities for a synergism to exist
between the two drugs for example penicillin + streptomycin.
• Additive Effect: When two antibiotics agents with the same mechanisms of action are
used.
• Antagonism: The effect of two or more drugs such that the combined effect is less than
the sum of the effects produced by each agent separately
             o Bacteriostatic antibiotics are antagonistic to bactericidal agents.
            o For example, chloramphenicol has been shown to antagonize the bactericidal
activities of penicillin in the treatment of Pneumococcal meningitis.
• Selective Toxicity: The ability of a drug to be more toxic to the invader than to the host.
              o This is a useful property of antimicrobial drugs.
• Therapeutic Index: A measure of drug safety obtained by comparing the amount of the
drug that produces an effective response to the amount that produces a toxic response.
            o It is calculated by dividing the lethal dose by the minimum effective dose.
Therapeutic index= Lethal Dose LD50
Effective Dose ED50
            o A large number indicates a wide margin of safety
           o A small number indicates a small margin of safe
A drug with a higher therapeutic index is safer than one with a lower therapeutic index.
Resistance to Antibacterial Drugs
Antimicrobial Resistance
• This is the capacity of bacteria to survive exposure to a defined concentration of an
antimicrobial substance.
           o Bacteria are said to be resistant if their growth is not halted by the maximum level of
an antibiotic that is tolerated by the host.
           o Many organisms have adapted, through spontaneous mutation or acquired resistance
and selection, and developed more virulent strains.
          o Many of these mutations/adaptations.    are resistant to multiple antibiotics.
• Antibiotic resistance in bacteria spreads in three ways:
         o Transfer of bacteria between people
ƒ Resistance in bacterial populations can be spread from person to person by
bacteria, from bacterium to bacterium by plasmids, from plasmid to plasmid (or
chromosome) by transposons.
        o Transfer of resistance genes between bacteria (usually on plasmids)
ƒ Plasmids are extra chromosomal genetic elements that can replicate independently
and can carry genes coding for resistance to antibiotics.
ƒ The main method of transfer of genes from one bacterium to another is by
plasmids. The bacterium forms a connecting tube with other bacteria through
which the plasmids pass.
       o Transfer of resistance genes between genetic elements within bacteria (on
transposons)
ƒ Transposons are stretches of deoxyribonucleic acid (DNA) that can be transposed
from one plasmid to another, from a plasmid to a chromosome or vice versa.
Mechanisms of Resistance to Antibiotics
• Bacteria have evolved numerous strategies for resisting the action of antibiotics and
antibacterial agents.
• This is particularly true of those bacteria that are antibiotic producers.
• Bacteria that produce antibiotics do so to gain a selective advantage over other,
competing microbes in their natural environment.
• If they were sensitive to their own metabolic products, such a selective advantage would
be lost.
• Bacteria may display antibiotic resistance by one or more of the following mechanisms:-
        o They may lack a target for the antibiotic
ƒ Chlamydia does not have peptidoglycan and are not susceptible to the action of
penicillins.
       o The antibiotic target may be inaccessible
ƒ Peptidoglycan in gram-negative bacteria is inaccessible to penicillins that cannot
penetrate the gram-negative outer membrane.
ƒ Efflux pumps can actively pump out antibiotics from cells.
ƒ Gram-negative bacteria resist the activity of tetracyclines by this important
mechanism.
         o The antibiotic target may be modified to prevent the action of the drug
ƒ Trimethoprim resistance is manifest by alterations in the enzyme target

ƒ Quinolone resistance is affected by point mutations in the DNA gyrase, which
prevent binding of the drug to its target.
o The antibiotic may be chemically modified or destroyed
ƒ Important examples include the huge range of b-lactamases and the various
aminoglycosides-modifying enzymes.
ƒ The b-lactam bond can be hydrolyzed by a large family of enzymes known as the
b-lactamases. Some b-lactamases have a preferential activity against penicillins
and these are referred to as penicillinases. Cephalosporinases are more active
against cephalosporins.
ƒ Chloramphenicol resistance is most often manifest by acetylation by the
chloramphenicol acetyl transferase enzyme.

📔Bacteria may elaborate alternative pathways, avoiding the drug target;
ƒ Staphylococcus aureus results from the production of an additional penicillin
binding protein 2, which is not susceptible to inhibition by penicillins.

Classification of Antimicrobial Drugs

• Antimicrobial drugs can be classified in a number of ways, according to:
    
        o Their chemical structure
ƒ β-Lactams, aminoglycosides
       o Mechanism of action
ƒ Cell wall synthesis inhibitors, or activity against
       o Types of organisms
ƒ Bacteria, fungi, viruses

Classification of Antimicrobial Drugs by Mechanism of Action

• Inhibitors of cell wall synthesis
      o β-lactam antibiotics for example Penicillin, Cephalosporins and Cephamycins
• Inhibitors of protein synthesis
     o Aminoglycosides, Tetracycline, Macrolides and Chloramphenicol
• Inhibitors of nucleic acid synthesis
     o Antimicrobial agents who interfere with the synthesis or action of folate for example
Sulphonamides and Trimethoprim
• Antimicrobial agents affecting topoisomerase
o Quinolones

Handouts

Classification of Antibiotics According to their Chemical Structure Class (chemical structure) Mechanism of action Examples

1.B-lactam antibiotics
Penicillins
   Cephalosporins
      Carbapenems

Target is
Inhibit bacterial cell wall
synthesis

Penicillins
Penicillin G
    Amoxicillin
      Flucloxacillin

Cephalosporins
Cefoxitin
   Cefotaxime
      Ceftriaxone

Carbapenem
Imipenem

Macrolides Inhibit bacterial protein
synthesis
Erythromycin , Azithromycin , Clarithromycin

Tetracyclines Inhibit bacterial protein
synthesis
• Tetracycline
• Minocycline
• Doxycycline
• Lymecycline
Fluoroquinolones Inhibit bacterial DNA
synthesis
• Norfloxacin
• Ciprofloxacin
• Enoxacin
• Ofloxacin
Sulphonamides Blocks bacterial cell
metabolism by inhibiting
enzymes
• Co-trimoxazole
• Trimethoprim
Aminoglycosides Inhibit bacterial protein
synthesis
• Gentamicin
• Amikacin
Imidazoles Inhibit bacterial DNA
synthesis
• Metronidazole
Peptides Inhibit bacterial cell wall
synthesis
• Bacitracin
Lincosamides Inhibit bacterial protein
synthesis
• Clindamycin
• Lincomycin
Other Inhibit bacterial protein
synthesis
• Fusidic acid
• Mupirocin