MCH

• Human beings are susceptible to many infectious microorganisms like bacteria, virus, fungi and other protozoans from an early age
• Before 20th century there was no proper treatment for diseases
• Diseases caused by bacteria such as Mycobacterium tuberculosis (Mycobacterium leprae) etc although were not identified but the use of antimicrobial agents for the treatment of various diseases was practiced even before the discovery of antibiotics
• Chemotherapy


  The treatment of systemic or local infections caused by microorganisms using chemotherapeutic agents (antibiotics or antimicrobials)
• Paul Ehrlich is regarded as the Father of Modern Chemotherapy and was awarded the Nobel Prize for his contributions in the field of chemotherapy
• Domagk and colleagues were effectively continuing the work of Paul Ehrlich because the sulfa drugs were inspired by dyes that were used to selectively stain bacterial cells
• Sulfonamides were the first truly effective, broad spectrum antimicrobials in clinical use and are still in use today, but they were largely superseded by the discovery of penicillin observed on a contaminated Petri dish by Alexander Fleming in 1928
• Broad classification of Antibacterial agents based On its mode of action

  • Inhibitors of cell wall synthesis
  • Disrupters of cell membranes
  • Inhibitors of protein synthesis
  • Inhibitors of nucleic acid synthesis
  • Antimetabolites and other antibacterial agents

  
• Sulfonamides


  Derived from p-aminobenzenesulfonamide, commonly referred to as sulfa drugs
• The sulfonamides are synthetic bacteriostatic antibiotics with a wide spectrum against most gram-positive and many gram-negative organism
• The sulphonamide drugs were the first effective totally synthetic chemotherapeutic agents to be employed systemically for the prevention in human beings
• The advent of penicillin and subsequently of other antibiotics has diminished the usefulness of sulphonamides
• Salvarsan was superseded by the sulfonamide prodrug Prontosil discovered by Gerhard Domagk a bacteriologist who used the drug to save his daughter's arm from amputation
• Nomenclature of Sulfonamides


  • Antibacterial that are aniline-substituted sulfonamides (i.e sulfanilamides)
  • Prodrugs that react to generate active sulfanilamides (i.e. sulfasalazine)
  • Non-aniline sulfonamides (i.e. mafenide acetate)
• Mechanism of action of Sulfonamides

  Bacteria synthesize their own folic acid (FA) of which p-aminobenzoic acid (PABA) is a constituent, and is taken up from the medium. Sulfonamides, are structural analogues of PABA, inhibit bacterial folate synthase and formation of folate get inhibited.
• Therapeutic uses of Sulfonamides


  • UTI: Sulfisoxazole; Sulfamethoxazole
  • Acute toxoplasmosis: Sulfadiazine+ pyrimethamine (DHFR inhibitor)
  • Malaria: Sulfadioxine + pyrimethamine
  • Ulcerative colitis, Inflammatory bowel diseases: Sulfasalazine
  • Bacterial Conjunctivitis: Sodium sulfacetamide
  • Burn infection: silver sulfadiazine
• Classification of Sulfonamides based on pharmacokinetics


  • Orally absorbable: Short acting, Intermediate acting, Long acting
  • Orally non-absorbable: Sulfasalazine
  • Topical: Sodium sulfacetamide, Silver sulphadiazine, Mafenide acetate
• Structure-activity relationship of Sulfonamides

  • Sulphanilamide skelton is the minimum structure requirement for antibacterial activity
  • Sulfur should be directly linked to the benzene
  • Strong electron withdrawing features by the aromatic SO2 moiety enhances the acidity of the two H-atoms linked to the N-atom
  • The active form of sulphonamide is the ionized form and maximum activity is observed between pKa-6.6 to 7.4
  • The free –NH2 group should para to the sulphonamide group. Its substitution at ortho or meta position destroy activity
  • Any substitution at free –NH2 group either form prodrug or in loss of activity
  • Substitution in the benzene ring of sulphonamide gives inactive compound
  • Exchange of the –SO2NH group by –CONH reduces the activity
  • Di substitution of sulphonamide N-atom leads to inactive compounds

  
• Classification of antibiotics based on chemical structure

  • B-lactam antibiotics: Penicillins, cephalosporin
  • Aminoglycoside antibiotics: Streptomycin, neomycin, kanamycin, Gentamicin, Tobramycin, Amikacin
  • Tetracycline antibiotics: Tetracycline, Demeclocycline, Doxycycline
  • Peptide antibiotics: Bacitracin, Polymixin, Vancomycin
  • Macrolide antibiotics: Erythromycin, Roxithromycin, Clarithromycin
  • Unclassified antibiotics: Chloramphenicol, Cycloserine
• 1. lactam antibiotics


  • Antibiotics that posses the b-lactam (a four membered cyclic amide) ring structure are the dominant class of agents currently used for chemotherapy of bacterial infections
  • The first antibiotic to be used in therapy is Penicillin (Penicillin G or penicillin), and a close biosynthesis relative Phenoxy methyl penicillin (Penicillin V) remain the agents of choice for the treatment of infections caused by most specieses of Gram-positive bacteria
  • Chemical modifications of naturally occurring penicillins and cephalosporins have provided semi synthetic derivatives
• Mechanism of action of B-lactam antibiotics


  • Bacterial cell wall consists of a heteropolymeric component which provides rigid mechanical stability by virtue of its highly cross-linked lattice wise structure
  • Penicillins and cephalosporins acylate serine moiety of specific bacterial D-transpeptidase and inhibit transpeptidation process
  • Bacterial D-alanine carboxypeptidases are also inhibited by B-lactam antibiotics

  
• Penicillin


  • A member of B-lactam antibiotics and can be considered as the amido derivatives of the 6-aminopenicillanic acid
  • In the basic skeleton, thiazolidine ring is fused with a beta-lactam ring which is a 4 membered cyclic amide
  • Commercial production of biosynthetic penicillins today depends chiefly on various strains of penicillium notatum and penicillium chrysogenum
• Numbering systems for the fused heterocyclic system of penicillin

  • Chemical Abstract system: Numbering starts from sulfur atom
  • USP system: Numbering starts from nitrogen atom
• Penicillin


  Consists of a beta-lactam ring fused with a thiazolidine ring, which is essential for its antibacterial activity
• The free penicillins are not suitable for oral or parental administration, hence in the form of their sodium and potassium salts
• Modification at C-6 position of penicillin

  • Carboxamido derived moieties are only allowed
  • Sulphonation or phosphoramide containing substituents are devoid of antibacterial activity
  • Increased stability towards acid catalyzed hydrolysis by substitution of an electron withdrawing group at alpha-position
  • Increased resistance to beta-lactamase by increasing steric hindrance at the alpha-carbon of acyl group

  
• Incorporation of a polar group at Alpha-position of benzyl penicillin


  • Imparts clinical activity against gram-negative bacilli
  • Substitution of a para-hydroxyl group onto the phenyl ring can balance the adverse polar effect of ionizable substituents
• Ureido penicillins


  • Contain a five-membered cyclic urea system joined by N-acylation to the Alpha-amino substituents of ampicillin
  • Impart improved penetration into gram-negative species and are more potent than ampicillin
• Cephalosporin


  A member of beta-lactam antibiotics, consists of a six membered dihydrothiazine ring fused with a beta-lactam ring
• Modification at C-7 position of cephalosporin

  • Acylation of amino group with carboxylic acid derivatives gives high antibacterial activity for gram-positive bacteria
  • Substituents on the phenyl ring can be replaced with other heterocycles to improve spectrum of activity and pharmacokinetic properties
• Modification at C-3 position of cephalosporin


  • Replacement of acetoxy group with -CH2, -Cl results in orally active compounds
  • Pyridine, imidazole groups show improved activity against Pseudomonas aeruginosa
  • Displacement of acetoxy group with azide ion yields derivative with relatively low gram negative activity
  • Aromatic thiols result in an enhancement of activity against gram-negative bacteria with improved pharmacokinetic properties

  
• Carbapenems


  Thienamycin and Imipenem have broad spectrum, antimicrobial activity and ability to inactivate beta-lactamase
• Monobactams


  A class of monocyclic beta-lactam antibiotics discovered from fermentation of unusual microorganisms
• Beta-lactamase inhibitors


  • Drugs given in combination with a beta-lactam antibiotic to inhibit the activity of beta-lactamase enzymes
  • Clavulanic acid is a suicide inhibitor that covalently bonds to a serine residue in the active site of beta-lactamase, permanently inactivating the enzyme
• Monobactams


  Aztreonam disodium, Tigemonam disodium
• Discovery of monobactams


  Fermentation of unusual microorganism led to discovery of a class of monocyclic B-lactam antibiotics, named monobactams
• 1. lactamase inhibitors


  Clavulanic acid, Sulbactum, Tazobactum
• Beta-lactamase inhibitor


  A drug given in combination with a b-lactam antibiotic to inhibit the activity of b-lactamase enzymes
• Clavulanic acid


  A suicide inhibitor that covalently bonds to a serine residue in the active site of the beta-lactamase, restructuring the clavulanic acid molecule into a more reactive species that is attacked by another amino acid in the active site, permanently inactivating the enzyme
• Aminoglycosides are one of the class of antibiotics which are basically bactericidal in nature