Antimicrobial agent

• Antibiotic discovery and development
• Antimicrobial agent


  Agents that act against microbial organisms
• Ideal antimicrobial agent


  • It should be able to kill the microbial agent or inhibit its growth
  • It must have a broad spectrum of activity
  • It should not cause any damage or adverse effect to the patient
  • It should remain stable when stored in either a solid or liquid form
  • It should be able to remain in specific body tissues long enough for it to be effective
  • It should be able to kill the organism or inhibit its growth before it has had a chance to mutate and develop resistance
  • It must exhibit selective toxicity - it must be toxic to the microbial cell but not to the host's cells
• Broad spectrum antibiotics


  • Tetracyclines
  • Phenicols
  • Fluoroquinolones
  • Third generation and Fourth Generation Cephalosporins
• Narrow spectrum antibiotics


  • Glycopeptides and bacitracin (Gram-positive Bacteria)
  • Polymixins (Gram-negative Bacteria)
  • Aminoglycosides and sulfonamides (Aerobic organism)
  • Nitroimidazoles (Anaerobes)
• Bactericidal


  Capable of killing the microorganisms
• Bacteriostatic


  Only inhibit the growth of the organism
• Local antibiotic


  Limits its action at the site where it is administered
• Systemic antibiotic


  Affects several body systems
• Mechanisms of action of antibiotics

  • Inhibition of cell wall synthesis (β-lactams, glycopeptides, bacitracin)
  • Inhibition of protein synthesis (aminoglycosides, tetracyclines, macrolides, lincosamides, chloramphenicol, oxazolidinones)
  • Inhibition of nucleic acid synthesis (rifamycins, fluoroquinolones)
  • Inhibition of folic acid synthesis (sulfonamides, sulfones, trimethoprim)
  • Inhibition of mycolic acid synthesis (isoniazid)
  • Disruption of cell membrane (polymyxins)
• Antimicrobial resistance is a major public health concern as microorganisms develop mechanisms to resist the effects of antimicrobial agents
• Microorganisms can develop antimicrobial resistance through various mechanisms such as enzymatic inactivation, target modification, decreased permeability, and efflux pumps
• Administered topical agents such as topical ointments or eye drops can act systemically - an antibiotic is one that affects several body systems
• Mode of action


  Different antibiotics have different modes of action, owing to the nature of their structure and degree of affinity to certain target sites within bacterial cells
• Antibiotics by mode of action

  • β-lactams (penicillins, cephalosporins, monobactams, carbapenems)
  • Glycopeptides (vancomycin)
  • Bacitracin
  • Fluoroquinolones (ciprofloxacin, levofloxacin, moxifloxacin)
  • Rifamycins (rifampin)
  • Polymyxins (polymyxin B, colistin)
  • Aminoglycosides
  • Tetracyclines
  • Macrolides
  • Lincosamides
  • Chloramphenicol
  • Oxazolidinones
  • Sulfonamides
  • Sulfones
  • Trimethoprim
  • Isoniazid
• Agents that interfere with the synthesis of bacterial cell wall


  • They act by inhibiting the different stages of peptidoglycan synthesis or by destroying already formed peptidoglycan by activating autolytic enzymes
  • The most commonly used are the β-lactam antibiotics as exemplified by penicillins and cephalosporins
  • Other examples: Bacitracin & Vancomycin
• Agents that alter the function or permeability of the cell membrane

  • Cell membranes are important barriers that segregate and regulate the intra- and extracellular flow of substances
  • A disruption or damage to this structure could result in leakage of important solutes essential for the cell's survival
  • Found in both Eukaryotic and Prokaryotic Cells, the action is often poorly selective and can be often be toxic for systemic use in the mammalian host
  • These agents initially act by disrupting the outer membrane structure enabling them to enter the cell and inhibit metabolic processes in the bacterial cell
  • Examples: Polymyxin and Lipopeptide (Daptomycin)
• Agents that inhibit Protein Synthesis

  • Protein synthesis is carried out typically by Ribosomes, which translates mRNA into proteins
  • These agents bind with the ribosomes, either the 50 S or the 30S ribosomal sub-units or both
  • As a result, bacteria are unable to make proteins and are bacteriostatic
  • Both 50s and 30s targets: Gentamycin, Kanamycin
• Agents that Act on the Nucleic Acid


  • DNA and RNA are keys to the replication of all living forms, including bacteria
  • Agents that inhibit DNA topoisomerases - topoisomerase enzymes (types I and II) are essential for DNA synthesis and are critical enzymes involved in protein translation and cell replication
  • Topoisomerase II (DNA Gyrase) is found only in prokaryotic organisms and is essential for their survival
  • Examples: Quinolones have been found to be most effective against DNA gyrase
  • Agents that inhibit RNA synthesis: Agents that act by interfering with the β-subunit of an RNA polymerase that is needed for RNA synthesis
  • Example: Rifampicin - first-line drug used for treatment of Tuberculosis (inhibits bacterial RNA synthesis)
• Nucleobases


  Adenine, Guanine, Thymine, Ribonucleic acid (RNA)
• Topoisomerases


  • Enzymes (types I and II) essential for DNA synthesis
  • Effective against Type II (DNA Gyrase) - found in Prokaryotes
  • Prevention of DNA synthesis
• RNA polymerase


  • Drug binds with β-subunit of an RNA polymerase
  • Inhibits RNA Synthesis, causes interference of the normal cellular processes, compromise bacterial multiplication and survival
• Agents that inhibit Microbial Metabolic Pathways


  • These agents interfere with the metabolic pathways crucial for the survival of the microorganisms
  • Trimethoprim and sulfonamides are antibiotics that interfere with the folic acid metabolism
  • They act as competitive inhibitors of tetrahydrofolic acid which is important in the synthesis of DNA, RNA, and bacterial cell wall proteins
  • Bacteria cannot synthesize preformed folic acid from the environment and thus must synthesize their own
  • Sulfonamides act specifically by inhibiting formation of dihydrofolic acid
  • Trimethoprim inhibits formation of tetrahydrofolic acid by inhibiting the enzyme dihydrofolate reductase
• Bacteria metabolize para-aminobenzoic acid (PABA) + Pteridine precursors to form Dihydrofolic acid and then Tetrahydrofolic acid, which is essential for synthesis of DNA, RNA, and bacterial cell wall proteins
• Sulfonamides antagonize the formation of Dihydrofolic acid

  Trimethoprim antagonizes the enzyme dihydrofolate reductase, thus inhibiting the formation of Tetrahydrofolic acid
• Drug resistance


  • Growing concern in the field of infection control
  • Microorganisms developed resistance - not affected anymore by antibiotics
• Intrinsic (innate) resistance


  • A stable genetic property that is encoded in the chromosome of the organism and shared by all strains of the species
  • The innate ability of a bacterial species to resist activity of a particular antimicrobial agent through its inherent structural or functional characteristics, which allow tolerance of a particular drug or antimicrobial class
• Acquired resistance


  • Resistance arising from the ability of an organism to resist an antimicrobial drug to which the species, as a whole, is a naturally susceptible
  • It is not normally encoded in the chromosome of the organisms but developed in the course of time due to constant exposure to the antimicrobial agent involved
  • It can be due to chromosomal mutation or the result of genetic exchange between organisms
• Factors contributing to development of antimicrobial resistance

  • Overuse of broad-spectrum antibiotics due to over-prescription
  • Incorrect diagnosis
  • Unnecessary restriction of antibiotics
  • Indiscriminate or improper use of antibiotics by the patient
  • Use of antibiotics in agriculture and livestock
• Acquired resistance


  Development of resistance arising from the ability of an organism to resist an antimicrobial drug to which the species, as a whole, is naturally susceptible
• Acquired resistance is not normally encoded in the chromosome of the organisms but developed in the course of time due to constant exposure to the antimicrobial agent involved
• Acquired resistance can be due to chromosomal mutation or the result of genetic exchange between organisms
• Factors that contribute to the development of antimicrobial resistance of microorganisms

  • Overuse of broad-spectrum antibiotics due to over-prescription
  • Incorrect diagnosis
  • Unnecessary restriction of antibiotics
  • Indiscriminate or improper use of antibiotics by the patient
  • Use of antibiotics as additives to livestock feeds to improve the growth of the animals
• Transformation


  The simplest and the earliest form of genetic exchange studied, where naked or free microbial DNA inserts itself into the DNA of the same species
• Transduction


  The transfer of genetic material by a bacteriophage
• Conjugation


  The transfer of genetic material through the sex pilus, where what is transferred to another bacterium is an extrachromosomal DNA called plasmid, and the resistance gene is carried by the plasmid
• Mechanisms of genetic exchange in bacteria

  • Transformation
  • Transduction
  • Conjugation
• Drug modification or inactivation

  A resistance code for enzymes that can alter the chemical structure of the antibiotic, leading to its inactivation, or the products of the resistance genes may cause hydrolysis of the antibiotic thereby destroying it
• Beta-lactamase enzymes inactivate the drug before it enters the bacterial cell through hydrolysis
• This is the most common mechanism of beta-lactam resistance and is the mechanism involved in the resistance of certain microorganisms to penicillins and cephalosporins