Antibiotics and Antimicrobials

• Antibiotics and antimicrobials are substances from microorganisms or made synthetically.
• These substances inhibit or destroy microorganisms, even in low concentrations.
• Natural sources of antibiotics include fungi and bacteria. Penicillin comes from the fungus Penicillium for example.
• Antibiotics treat infectious diseases.
• Ideal antimicrobials kill or inhibit microbial growth, have a broad activity spectrum, do not harm the patient, are stable in storage (solid or liquid), remain effective in body tissues, kill or inhibit organisms before mutation, and exhibit selective toxicity.

Spectrum of Activity

• Broad-spectrum antibiotics target a wide range of microorganisms.
• Narrow-spectrum antibiotics target a limited number of microorganisms.

Antimicrobial Activity

• Bactericidal antibiotics kill microorganisms.
• Bacteriostatic antibiotics only inhibit microorganism growth.
• Bactericidal agents are preferred over bacteriostatic drugs in the choice of antibiotics.

Absorbability from Site of Administration

• Locally-acting antibiotics limit their action to the administration site, for example, topical ointments or eye drops.
• Systematically-acting antibiotics affect several body systems when administered intramuscularly or intravenously.

Mechanism of Action

Agents that Interfere with Bacterial Cell Wall Synthesis

• Beta-lactam antibiotics (penicillins and cephalosporin) inhibit immature peptidoglycan's conversion to mature peptidoglycan by directly inhibiting bacterial transpeptidase, also called penicillin-binding proteins (PBPs).
• Glycopeptides (e.g., vancomycin) inhibit transglycosylase and transpeptidase enzymes involved in peptidoglycan synthesis.

Agents that Alter Cell Membrane Function/Permeability

• Includes cationic, anionic, neutral agents, and antifungal drugs.
• Polymyxin B and colistemethate (polymyxin E) are cationic agents that disrupt the outer membrane, allowing entry into the cell to inhibit metabolic processes.
• Antifungal drugs (nystatin, amphotericin B) alter cell membrane permeability.
• Azoles (clotrimazole, ketoconazole, miconazole, fluconazole) interfere with ergosterol synthesis in fungal cell membranes.

Agents that Inhibit Protein Synthesis

• Targets the 30S or 50S ribosomal subunits.
• Inhibitors of the 30S ribosomal subunit primarily interfere with the initiation process, for example, aminoglycosides and tetracycline.
• Aminoglycosides cause non-functional complexes and misreading.
• Spectinomycin binds to a protein in the 30S ribosome different from aminoglycosides.
• Agents binding to the 50S ribosomal subunit inhibit the elongation process, including chloramphenicol, macrolides, and lincinoids.
• Chloramphenicol inhibits peptide bond formation by binding to peptidyl transferase, effective against gram-positive and gram-negative organisms and is bacteriostatic.
• Macrolides interfere with peptidyl transferase, inhibiting its reaction and translocation, and erythromycin inhibits gram-positive and gram-negative bacteria.
• Lincinoids or lincosamines, like macrolides, bind to both 30S and 50S ribosomal subunits, including gentamycin and kanamycin.

Agents that Inhibit Microbial Metabolic Pathways

• Trimethoprim and sulfonamides interfere with folic acid metabolism, acting as competitive inhibitors that are important in the synthesis of DNA, RNA, and bacterial cell wall proteins.

Mechanisms of Drug Resistance

• Drug resistance is a growing concern.
• Organisms develop resistance when antibiotics no longer affect them, either through innate or acquired mechanisms.
• Intrinsic resistance is a stable genetic property encoded in the chromosome and shared by all strains of the species.
• Acquired resistance arises from the organism's ability to resist an antimicrobial drug to which it is normally susceptible, developed over time due to constant exposure to the agent but not normally encoded on the chromosome.

Factors that Contribute to Antimicrobial Resistance

• Overuse of broad-spectrum antibiotics by over-prescription.
• Incorrect diagnosis leading to inappropriate antibiotic use.
• Unnecessary prescription of antibiotics when they’re not needed.
• Indiscriminate/improper antibiotic use by patients.
• Using antibiotics as additives in livestock feeds to improve growth.

Mechanisms of Drug Resistance

• Drug modification or inactivation occurs when resistance genes code for enzymes that alter or inactivate the antibiotic, or cause its hydrolysis.
• Prevention of cellular uptake or efflux prevents the antibiotic from accumulating in the bacterial cell; efflux pumps effectively remove antimicrobials.
• Modification of target sites involves changing the structure of antimicrobial targets, preventing the antibiotic from binding effectively.

Examples of Antimicrobial Target Sites

• Modified peptides sub-units of peptidoglycan involve glycopeptides.
• Modified Ribosome sub-units involve Macrolides, tetracyclines, aminoglycosides.
• Modified Metabolic enzymes involve Sulfa drugs, sulfones, trimethoprim.
• Modified Lipopolysaccharide structure involve polymyxins.
• Modified DNA gyrase involve fluoroquinolones.
• Modified RNA polymerase involve rifampin. Overproduction or bypass of target enzymes: bacteria overcome antibiotics by overproducing the target enzyme, ensuring enough free enzyme for essential reactions. Target mimicry: bacteria produce proteins similar in structure to the antibiotic target sites, causing the antimicrobial to bind the new proteins instead of the target protein.