ANTIMICROBIAL DRUGS
Hugo Vicente Ralde, M.D.
Dept. Microbiology - PIFM.
ICB - UAG.
Definition of an Antibiotic

Substance produced by a microorganism or a similar product produced wholly (synthetic) or partially (semi-synthetic) by chemical synthesis and in low concentrations inhibits the growth of or kills microorganisms.
Characteristics of an Ideal Chemotherapeutic Drug.
(There are No Perfect Drugs)

1. Selective Toxicity Against Target Pathogen But Not Against Host.
Would like LD50 to be high and Minimal Inhibitory Concentration (MIC) and/or Minimal Bactericidal Concentration (MBC) to be low.

LD50 = Lethal Dose 50%; Measure of drug toxicity/Lethality against host.
MIC; Measure of the concentration of the antibiotic necessary to inhibit growth of the target pathogen.
MBC; Measure of the concentration of the antibiotic necessary to kill the target pathogen.
2. Favorable Pharmacokinetics: Survive in high concentration and reach the target site (site of infection).
Pharmacokinetics: Action of drugs in the body over a period of time including:
Absorption
Distribution
Localization in tissues
Biotransformation (biochem. Alterations).
Excretion .

3. Would like the Drug to be:
Bactericidal (Microbicidal) : Kill microbes (-cidal = death or killing)
Bacteriostatic: Stops growth of microorganisms without killing them (-static = stationary; at rest; stasis).
Spectrum of Activity (Broad vs. Narrow). Coordinated with Diagnosis

For example:
A broad-spectrum antibiotic would be indicated against a polymicrobial infection, e.g., an intrabdominal anaerobic infection.

A narrow spectrum antibiotic would be ideal for an infection caused by a single pathogen, e.g., a staphylococcal skin infection.
Lack of “Side Effects”

Able to Cross Outer and Cytoplasmic Membranes.
No or Low Level of Antibiotic Resistance in Target Pathogen and Lack of Cross-Resistance in Closely Related Strains.

Resistant to Inactivation by Microbial Enzymes.
Basic Mechanisms of Antibiotic Action and Resistance.
Five Basic Mechanisms of Antibiotic actions Against Bacterial Cells:
1. Inhibition of Cell Wall Synthesis (most common mechanism).
2. Inhibition of Protein Synthesis (Translations) (second largest class)
3. Alteration of Cell Membranes
4. Inhibition of Nucleic Acid Synthesis
5. Antimetabolite Activity.
1. Inhibition of Cell Wall Synthesis
A. Beta-Lactams : Inhibition of peptidoglycan synthesis (bactericidal)
Resistance:
Fails to cross membrane (gram negatives)
Fails to bind to altered PBP´s
Hydrolysis by beta-lactamases.

B. Vancomycin: Disrupts peptidoglycan cross- linkage.
Resistance:
fails to cross gram negative outer membrane (too large)
some intrinsically resistant (pentapeptide terminus)
C. Bacitracin Disrupts movement of peptidoglycan precursors (topical use)
Resistance:
fails to penetrate into cell.



D. Antimycobacterial agents : Disrupt mycolic acid or arabinoglycan synthesis (bactericidal)
Resistance:
Reduced uptake
Alteration of target sites.
2. Inhibition of Protein Synthesis (Translation)
30S Ribosome site
A. Aminoglycosides : Irreversibly bind 30S ribosomal proteins (bactericidal)
Resistance:
Mutation of ribosomal binding site
Decreased uptake
Enzymatic modification of antibiotic.


B. Tetracyclines: Block tRNA binding to 30S ribosome-mRNA complex (b-static)
Resistance:
Decreased penetration
Active efflux of antibiotic out of cell
Protection of 30S ribosome.
50S Ribosome site

A. Chloramphenicol : Binds peptidyl transferase component of 50S ribosome, blocking peptide elongation (bacteriostatic)
Resistance:
Plasmid-encoded chloramphenicol transferase
Altered outer membrane (chromosomal mutations).
B. Macrolides : Reversibly bind 50S ribosome, block peptide elongation (b-static)
Resistance:
Methylation of 23S ribosomal RNA subunit
Enzymatic cleavage (erythromycin esterase)
Active efflux


C. Clindamycin: Binds 50S ribosome, blocks peptide elongation;
Inhibits peptidyl transferase by interfering with binding of amino acid-acyl-tRNA complex.
Resistance:
Methylation of 23S ribosomal RNA subunit.
3. Alteration of Cell Membranes
A. Polymyxins (topical) Cationic detergent-like activity (topical use).
Resistance:
Inability to penetrate outer membrane.
B. Bacitracin (topical) Disrupts cytoplasmic membranes.
Resistance:
Inability to penetrate outer membrane
4. Inhibition of Nucleic Acid Synthesis.
DNA Effects
A. Quinolones : Inhibit DNA gyrases or topoisomerases required for supercoiling of DNA; bind to alpha subunit.
Resistance:
Alteration of alpha subunit of DNA gyrase (Chromosomal)
Decreased uptake by alteration of porins (Chromosomal)
B. Metronidazole: Metabolic cytotoxic byproducts disrupt DNA
Resistance:
Decreased uptake
Elimination of toxic compounds before they interact.

RNA Effects (Transcription)
C. Rifampin: Binds to DNA-dependent RNA polymerase inhibiting initiation & Rifabutin of RNA synthesis.
Resistance:
Altered of beta subunit of RNA polymerase (chromosomal)
Intrinsic resistance in gram negatives (decreased uptake).

D. Bacitracin (topical) : Inhibits RNA transcription.
Resistance:
Inability to penetrate outer membrane.

5. Antimetabolite Activity

A. Sulfonamides & Dapsone: Compete with p- aminobenzoic acid (PABA) preventing synthesis of folic acid.
Resistance:
Permeability barriers (e.g., Pseudomonas)
B. Trimethoprim : Inhibit dihydrofolate reductase preventing synthesis of folic acid.
Resistance:
Decreased affinity of dihydrofolate reductase.
Intrinsic resistance if use exogenous thymidine.
C. Trimethoprim-Sulfamethoxazole synergism.