UNIT-1 ANTIBIOTIC.pptx UNIT 1 B.PHARM 601T

UNIT 1 B.PHARM BP601T

1. IIMT College of Pharmacy, Greater Noida Antibiotic Ms. Bharti Chauhan (ASSISTANT PROFESSOR ) Unit: I Subject Name- Medicinal Chemistry-III BP-601T B Pharm VI Sem

2. UNIT – I Antibiotic 08 Hours Antibiotics Historical background, Nomenclature, Stereochemistry, Structure activity relationship, Chemical degradation classification and important products of the following classes. β- Lactam antibiotics : Penicillin, Cepholosporins , β- Lactamase inhibitors, Monobactams Aminoglycosides : Streptomycin, Neomycin, Kanamycin Tetracyclines : Tetracycline, Oxytetracycline , Chlortetracycline, Minocycline, Doxycycline SYLLABUS

3. Introduction Introduction of antibiotics. Classification and mode of action β- Lactam antibiotics Introduction of synthetic antifungal agents Classification and mode of Penicillin, Cepholosporins , β- Lactamase inhibitors, Monobactams Structure activity relationship of β- Lactam antibiotics Introduction of Aminoglycosides : Streptomycin, Neomycin, Kanamycin Tetracyclines . Tetracycline, Oxytetracycline , Chlortetracycline, Minocycline , Doxycycline 3 CONTENT

4. Upon completion of the course student shall be able to 1. Understand the importance of drug design and different techniques of drug design. 2. Understand the chemistry of drugs with respect to their biological activity. 3. Know the metabolism, adverse effects and therapeutic value of drugs. 4. Know the importance of SAR of drugs. 4 COURSE OBJECTIVE

5. 5 COURSE OUTCOME CO No. CO STATEMENT LEVEL OF TAXONOMY CO1.1 History and Different types of antibiotics. Level I (Remembering) CO1.2 Mode and action and structure activity relationship of β- Lactam antibiotics Level II (Understanding) CO1.3 Use and adverse effect of β- Lactam antibiotics . Level III (Applying) After completion of this unit it is expected that students will be able to

6. 6 PROGRAMME OUTCOMES (POs) PO 1 Pharmacy Knowledge: Possess knowledge and comprehension of the core and basic knowledge associated with the profession of pharmacy, including biomedical sciences; pharmaceutical sciences; behavioral, social, and administrative pharmacy sciences; and manufacturing practices. PO 2 Planning Abilities: Demonstrate effective planning abilities including time management, resource management, delegation skills and organizational skills. Develop and implement plans and organize work to meet deadlines PO 3 Problem analysis: Utilize the principles of scientific enquiry, thinking analytically, clearly and critically, while solving problems and making decisions during daily practice. Find, analyze, evaluate and apply information systematically and shall make defensible decisions. PO 4 Modern tool usage: Learn, select, and apply appropriate methods and procedures, resources, and modern pharmacy-related computing tools with an understanding of the limitations.

7. 7 PROGRAMME OUTCOMES (POs) PO 5 Leadership skills: Understand and consider the human reaction to change, motivation issues, leadership and team-building when planning changes required for fulfillment of practice, professional and societal responsibilities. Assume participatory roles as responsible citizens or leadership roles when appropriate to facilitate improvement in health and wellbeing. PO 6 Professional Identity: Understand, analyze and communicate the value of their professional roles in society (e.g. health care professionals, promoters of health, educators, managers, employers, employees). PO 7 Pharmaceutical Ethics: Honour personal values and apply ethical principles in professional and social contexts. Demonstrate behavior that recognizes cultural and personal variability in values, communication and lifestyles. Use ethical frameworks; apply ethical principles while making decisions and take responsibility for the outcomes associated with the decisions.

8. 8 PROGRAMME OUTCOMES (POs) PO 8 Communication: Communicate effectively with the pharmacy community and with society at large, such as, being able to comprehend and write effective reports, make effective presentations and documentation, and give and receive clear instructions. PO 9 The Pharmacist and society: Apply reasoning informed by the contextual knowledge to assess societal, health, safety and legal issues and the consequent responsibilities relevant to the professional pharmacy practice PO 10 Environment and sustainability: Understand the impact of the professional pharmacy solutions in societal and environmental contexts, and demonstrate the knowledge of, and need for sustainable development PO 11 Life-long learning: Recognize the need for, and have the preparation and ability to engage in independent and life-long learning in the broadest context of technological change. Self access and use feedback effectively from others to identify learning needs and to satisfy these needs on an ongoing basis.

9. 9 CO-PO MAPPING The CO-PO mapping has been done with correlation levels of 3, 2, 1 and ‘-‘. The notation of 3, 2 and 1 denotes substantially (high), moderately (medium) and slightly (low). The meaning of ‘-‘is no correlation between CO and PO. PO PO 1 PO 2 PO3 PO4 PO5 PO6 PO7 PO8 PO9 PO 10 PO 11 CO1.1 3 - 1 3 - - - - 1 - - CO1.2 3 - 1 3 - - - - 1 - - CO1.3 3 - 1 3 - - - - 1 - -

10. 10 Topic Objective mapping with CO Name of Topic Objective of topic Mapping with CO Antibiotic β- Lactam antibiotics Aminoglycosides Tetracycline, Introduction, Mechanism Of Action of β- Lactam antibiotics Aminoglycosides Tetracycline Antibiotic CO1.1 Classificaion Classify the β- Lactam antibiotics Aminoglycosides Tetracycline Antibiotic CO1.2 Synthesis and SAR Structure activity relationship and Synthesis of β- Lactam antibiotics Aminoglycosides Tetracycline Antibiotic CO1.3 Mapping of Course Outcomes with Topic:

11. Subject covers pharmacology of various diseases and chemistry of drugs along with SAR and their uses. Student must have the knowledge of pharmacology of discussed diseases before going to chemistry of drugs used for the same . 11 ANTIBIOTICS (CO-1.1)

12. Antibiotic:   Substances derived from a microorganism or produced synthetically, that destroys or limits the growth of a living organism A drug used to treat  bacterial infections . Antibiotics have no effect on viral infections. Originally, an antibiotic was a substance produced by one microorganism that selectively inhibits the growth of another. Synthetic antibiotics, usually chemically related to natural antibiotics, have since been produced that accomplish comparable tasks. 12 ANTIBIOTICS (CO-1.1)

13. Classification of antibiotics Sources 1. Natural a. Fungi – penicillin, griseofulvin b. Bacteria – Bacillus sp. ( polymixin , bacitracin ) ; Actinomycetes (tetracycline, chloramphenicol , streptomycin) 2. Synthetic 13 ANTIBIOTICS (CO-1)

14. 15 ANTIBIOTICS (CO-1.1) History of Antibiotics (continue ..) Antibiotics have been used for millennia to treat infections, although until the last century or so people did not know the infections were caused by bacteria Various molds and plant extracts were used to treat infections by some of the earliest civilizations – the ancient Egyptians, for example, applied moldy bread to infected wounds It wasn’t until the late 19th century that scientists began to observe antibacterial chemicals in action. Paul Ehrlich, a German physician, noted that certain chemical dyes colored some bacterial cells but not others. He concluded that, according to this principle, it must be possible to create substances that can kill certain bacteria selectively without harming other cells

15. 15 ANTIBIOTICS (CO-1.1) History of Antibiotics (continue ..) In 1909, he discovered that a chemical called arsphenamine was an effective treatment for syphilis. This became the first modern antibiotic, although Ehrlich himself referred to his discovery as 'chemotherapy' – the use of a chemical to treat a disease The word 'antibiotics' was first used over 30 years later by the Ukrainian-American inventor and microbiologist Selman Waksman, who in his lifetime discovered over 20 antibiotics.

16. 15 ANTIBIOTICS (CO-1.1) History of Antibiotics (continue ..) Alexander Fleming was, it seems, a bit disorderly in his work and accidentally discovered penicillin. Upon returning from a holiday in Suffolk in 1928, he noticed that a fungus,  Penicillium notatum , had contaminated a culture plate of Staphylococcus bacteria he had accidentally left uncovered. The fungus had created bacteria-free zones wherever it grew on the plate. Fleming isolated and grew the mold in pure culture. He found that P. notatum  proved extremely effective even at very low concentrations, preventing Staphylococcus growth even when diluted 800 times, and was less toxic than the disinfectants used at the time..

17. 15 ANTIBIOTICS (CO-1.1) After early trials in treating human wounds, collaborations with British pharmaceutical companies ensured that the mass production of penicillin (the antibiotic chemical produced by P. notatum ) was possible. Following a fire in Boston, Massachusetts, USA, in which nearly 500 people died, many survivors received skin grafts which are liable to infection by Staphylococcus. Treatment with penicillin was hugely successful, and the US government began supporting the mass production of the drug. By D-Day in 1944, penicillin was being widely used to treat troops for infections both in the field and in hospitals throughout Europe. By the end of World War II, penicillin was nicknamed 'the wonder drug' and had saved many lives.

18. Difference between the bactericidal and bacteriostatic Tetracyclines Spectinomycin Sulphonamides Macrolides Chloramphenicol Trimethoprim Bactericidal Antibiotics Penicillins Cephalosporins • Fluoroquinolones (Ciprofloxacin) • Glycopeptides ( Vancomycin ) • Monobactams Carbapenems 16 ANTIBIOTICS (CO-1.1) Bacteriostatic Antibiotics

19. 16 ANTIBIOTICS (CO-1.2) Classifications of antibiotics

20. 16 ANTIBIOTICS (CO-1.2) Classifications of antibiotics

21. 16 ANTIBIOTICS (CO-1.2) Classifications of antibiotics

22. 16 ANTIBIOTICS (CO-1.2) Classifications of antibiotics

23. 16 ANTIBIOTICS (CO-1.2) Classifications of antibiotics

24. 16 ANTIBIOTICS (CO-1.2) Classifications of antibiotics

25. Mode action of antibiotics 16 ANTIBIOTICS (CO-1.1) Inhibitors of DNA synthesis Inhibitors of bacterial protein synthesis Inhibitors of bacterial cell wall synthesis Interference with metabolism Impairment of nucleic acids

26. 16 ANTIBIOTICS (CO-1) Inhibitors of DNA synthesis Inhibitors of bacterial protein synthesis Inhibitors of bacterial cell wall synthesis Interference with metabolism Impairment of nucleic acids

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33. 16 ANTIBIOTICS (CO-1.2) β- lactam antibiotics (beta- lactam antibiotics) are antibiotics that contain a beta- lactam  ring in their molecular structure. This includes penicillin derivatives ( penams ),  cephalosporins  ( cephems ),  monobactams ,  carbapenems  and  carbacephe

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35. Penicillin 16 ANTIBIOTICS (CO-1) Penicillin is a secondary metabolite produced by certain bacteria, which is used an antibiotic . A bacterial infection is caused by millions of tiny bacteria that are trying to survive and in multiply the body . An antibiotic attacks and kill these bacteria . Before the development of penicillin , many people suffered and died from bacterial infections that are no longer considered dangerous today

36. 16 ANTIBIOTICS (CO-1.1) HISTORY 1928 – ALEXANDER FLEMING Bread mold ( Penicillium notatum ) growing on petri dish 1939 – FLOREY , Chain, and Associates Began work on isolating and synthesizing large amounts of penicillin. 1941 – Introduced in antibacterial therapy 1944 – penicillin has been at the disposal of all people History ALEXANDER FLEMING   PROPERTIES Optically active Soluble in water. Acid resistant. Hydrolyzed by hot inorganic acid . Effective in treatment of respiratory track infection .

37. 16 ANTIBIOTICS (CO-1.1) Clasification Natural penicillin's penicillin G Penicillin VK 2.Beta lactase resistant penicillin's 3.Aminopenicillins penicillin G Penicillin VK Methicillin nafcillin Ampicillin amoxicillin 4.Carboxypenicillins 5.Ureidopenicillins 6.penicillin/ inihibitor combination Carcenicillin ticarcillin Mezlocillin piperacillin Ampicillin / sulbactam Ticarcillin / clavulanate

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40. 16 ANTIBIOTICS (CO-1) PenicillinV ( Phenoxymethylpenicillin ) Effective Against : • Gram positive + Less effective against Gram negative bacteria Treatment For : • Tonsillitis • Anthrax • Rheumatic fever • Streptococcal skin infections Characteristics : • Narrow spectrum • Should be given orally • Prone to beta- lactamase Penicillin G ( Benzylpenicillin ) Narrow spectrum antibiotic. Primarily to gram positive bacteria and few others, active agains , Cocci -Streptococci (except group D), Staph.aureus ; gram negative N.gonorrheoe and

41. 16 ANTIBIOTICS (CO-1.1) What is the difference between penicillin G and penicillin V ? Penicillin G is a natural penicillin that is produced directly from fermentation of Penicillium crysogenum . Penicillin V is a derivative of penicillin G and because of similarities in spectrum of activity, is considered a natural penicillin. Penicillin G  benzathine , potassium, procaine and sodium are currently available in the United States in parenteral formulations for intravenous or intramuscular use. Penicillin V potassium (also called phenoxymethyl  penicillin) is a more acid stable and can be administered orally.

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55. SAR OF PENICILLI ANTIBIOTICS (CO-1.3)

56. SAR OF PENICILLI 5/1/2024 Chandana majee BP-601T Med.Chem-III Unit-1 16 ANTIBIOTICS (CO-1.1)

57. SAR OF PENICILLI ANTIBIOTICS (CO-1.3)

58. ANTIBIOTICS (CO-1.3)

59. ANTIBIOTICS (CO-1.3) MECHANISM OF ACTION OF PENICILLIN Penicillin and other antibiotics in the beta-lactam family contain a characteristic four-membered beta-lactam ring. Penicillin kills bacteria through binding of the beta-lactam ring to DD- transpeptidase , inhibiting its cross-linking activity and preventing new cell wall formation. Without a cell wall, a bacterial cell is vulnerable to outside water and molecular pressures, which causes the cell to quickly die.  Since human cells do not contain a cell wall, penicillin treatment results in bacterial cell death without affecting human cells. Gram-positive bacteria have thick cell walls containing high levels of peptidoglycan, while gram-negative bacteria are characterized by thinner cell walls with low levels of peptidoglycan.  The cell walls of gram-negative bacteria are surrounded by a lipopolysaccharide (LPS) layer that prevents antibiotic entry into the cell. Therefore, penicillin is most effective against gram-positive bacteria where DD- transpeptidase activity is highest .

60. ANTIBIOTICS (CO-1.3) Nomenclature There are two types of numbering for the fused bicycling system of penicillin: whether which atom is number one Sulfur or Nitrogen. Penam nucleus is used in naming which comprise bicyclic system with the amide carbonyl group. Penicillin is named as 6-acylamino-2,2-dimethylpenam-3-carboxylic acid . Penicillanic acid nucleus: Which includes the 2,2-dimethyl and 3-carboxyl groups. Penicillin is named as 6- carbonylaminopenicillanic acid . Penicillin nucleus: Which includes 6-carbonyl aminopenicillanic acid. So Penicillin G is named benzylpenicillin if R is benzene ring

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66. ANTIBIOTICS (CO-1.3) Nomenclature

67. ANTIBIOTICS (CO-1.3) Stereochemistry The penicillin molecule contains three chiral carbon atoms at C-3, C-5 and C-6 All natural and synthetic penicillins have the same absolute configuration about these three centers The 6 carbon atom bearing the acyl amino group has the L-configuration, whereas the carbon to which the carboxyl group was attached has the D-configuration. The acyl amino group and carboxyl group are trans to each other, with the former and latter in the β orientation relative to penam ring. The absolute stereochemistry of the penicillins is designated as 35: 5R: 6R. The atoms composing the 6-aminopenicillanic acid are biosynthetically derived from two amino acids, Lcysteine and D-valine

68. ANTIBIOTICS (CO-1.3)

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76. 16 ANTIBIOTICS (CO-1.1) Mechanism of action penicillinen

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79. 16 ANTIBIOTICS (CO-1.1) β- Lactamase enzyme Beta- lactamases  are enzymes produced by bacteria that provide multi- resistance to  β- lactam antibiotics such as  penicillins ,  cephalosporins ,  cephamycins , and  carbapenems  ( ertapenem ), although carbapenems are relatively resistant to beta- lactamase .  In Gram-negative bacteria, β- lactamase enzymes that hydrolyze the amide bond of the four- membered β- lactam ring are the primary resistance mechanism,

80. 16 ANTIBIOTICS (CO-1.1) β- Lactamase inhibitors : Beta- lactamases  are a family of enzymes involved in bacterial resistance to beta- lacta antibiotics. They act by breaking the beta- lactam  ring that allows penicillin-like antibiotics to work. Beta- lactamase enzymes are produced by certain strains of the followingbacteria :  Bacteroides  species,  Enterococcus  species,  Hemophilus influenzae ,  Moraxella catarrhalis ,  Neisseria gonorrhoeae , and  Staphylococcus  species, either constitutively or on exposure to antimicrobials. Beta- lactamases cleave the beta- lactam ring of susceptible penicillins and cephalosporins , inactivating the antibiotic. Some antimicrobials ( eg , cefazolin and cloxacillin ) are naturally resistant to certain beta- lactamases .

81. 16 ANTIBIOTICS (CO-1.1) β- Lactamase inhibitors : Clavulanic  acid contains a beta- lactam ring and binds strongly to beta- lactamase at or near its active site, thereby hindering enzymatic activity. This protects other beta- lactam antibiotics from beta- lactamase catalysis, thereby enhancing their antibacterial effects.

82. Chandana majee BP-601T Med.Chem-III Unit-1 16 ANTIBIOTICS (CO-1.1) 5/1/2024 β- Lactamase inhibitors : Clavulanic  acid contains a beta- lactam ring and binds strongly to beta- lactamase at or near its active site, thereby hindering enzymatic activity. This protects other beta- lactam antibiotics from beta- lactamase catalysis, thereby enhancing their antibacterial effects .

83. Chandana majee BP-601T Med.Chem-III Unit-1 16 ANTIBIOTICS (CO-1.1) 5/1/2024 β- Lactamase inhibitors : Clavulanic  acid contains a beta- lactam ring and binds strongly to beta- lactamase at or near its active site, thereby hindering enzymatic activity. This protects other beta- lactam antibiotics from beta- lactamase catalysis, thereby enhancing their antibacterial effects .

84. 16 ANTIBIOTICS (CO-1.1) β- Lactamase inhibitors : Clavulanic  acid contains a beta- lactam ring and binds strongly to beta- lactamase at or near its active site, thereby hindering enzymatic activity. This protects other beta- lactam antibiotics from beta- lactamase catalysis, thereby enhancing their antibacterial effects .

85. 16 ANTIBIOTICS (CO-1.1) β- Lactamase inhibitors : Clavulanic  acid contains a beta- lactam ring and binds strongly to beta- lactamase at or near its active site, thereby hindering enzymatic activity. This protects other beta- lactam antibiotics from beta- lactamase catalysis, thereby enhancing their antibacterial effects .

86. 16 ANTIBIOTICS (CO-1.1) Clavulanic acid Clavulanic  Acid is a semisynthetic beta- lactamase inhibitor isolated from Streptomyces .  Clavulanic  acid contains a beta- lactam ring and binds strongly to beta- lactamase at or near its active site, thereby hindering enzymatic activit : .

87. 16 ANTIBIOTICS (CO-1.1) Clavulanic acid Clavulanic  Acid is a semisynthetic beta- lactamase inhibitor isolated from Streptomyces .  Clavulanic  acid contains a beta-lactam ring and inds strongly to beta-lactamase at or near its active site, thereby hindering enzymatic activit : .

88. 16 ANTIBIOTICS (CO-1.1) Clavulanic acid The combination of amoxicillin and  clavulanic acid  is  used to  treat certain infections caused by bacteria, including infections of the ears, lungs, sinus, skin, and urinary tract. Amoxicillin is in a class of medications called penicillin-like antibiotics. It works by stopping the growth of bacteria. .

89. 16 ANTIBIOTICS (CO-1.2) Clavulanic acid,  sulbactam , and  tazobactam Avibactam , vaborbactam , and  relebactam

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94. 16 β- LACTAM ANTIBIOTICS (PENICILLI) (CO-1.1)

95. 16 β- LACTAM ANTIBIOTICS (CO-1.1) The cephalosporins were isolated from the fungus Cephalosporium acremonium in 1948 by Pro Tzu, Newton, and Abraham (1953) Cephalosporins contain dihydrothiazine ring, while penicillin contains a tetrahydrothiazole ( thiazolidine ) ring The cephalosporins are much more acid stable than the corresponding penicillins . Cephalosporins can be divided into three classes: 1. Cephalosporin N: penicillin-like structure - a derivative of 6-aminopenicillanic acid. 2. Cephalosporin P: An acidic antibiotic, which is steroidal in nature 3 . Cephalosporin-C: It is a true cephalosporin and it is a derivative of 7 amino- cephalosporanic acid – semi synthetic derivatives Cephalosporins

96. 16 β- LACTAM ANTIBIOTICS (CO-1.1) Cephalosporins Cepham is the name given to the unsubstituted bicyclic lactam.

97. 16 β- LACTAM ANTIBIOTICS (CO-1.1) Classification Cephalosporins (Route of administration) Orally administered : cephalexin, cephradine, and cefaclor b. Parentrally administered : cephalothin, cephapirin, cephacetrile, and cefazedone. These agents are sensitive to β- lactamase c. Resistant to β- lactamase and parentrally administered : cefuroxime, cefamandole, cefoxitin d. Metabolically unstable : cephalothin and cephapirin

98. 16 β- LACTAM ANTIBIOTICS (CO-1.1) First generation cephalosporins - Cephalexin, cephadroxil, cephradine and cephalothine Second-generation cephalosporins - Cefaclor, cefamandole Third-generation cephalosporins – Cefotaxime, ceftizoxime Fourth generation – Cefepime, Cefpirome

99. 16 β- LACTAM ANTIBIOTICS (CO-1.1) Degradation of cephalosporins In prescence of strong acids - inactive lactone

100. 16 β- LACTAM ANTIBIOTICS (CO-1.1) SAR of cephalosporins 1 . 7-Acylamino substituents: Acylation of amino group generally increases the potency against gram-positive bacteria, but decreases gram-negative potency. Substituents on the aromatic ring that increases lipophilicity provide higher gram- positive activity and generally lower gram-negative activity . The phenyl ring in the side-chain can be replaced with other heterocycles with improved spectrum of activity and pharmacokinetic properties, and these include thiophene , tetrazole , furan, pyridine

101. 16 β- LACTAM ANTIBIOTICS (CO-1.1) SAR of cephalosporins 2. C-3 substituents: influences pharmacokinetic and pharmacological properties as well as antibacterial activity . Modification at C-3 position has been made to reduce the degradation of cephalosporins . ( i ) The benzoyl ester - improved gram-positive activity but lower gram-negative activity. (ii) Pyridine and imidazole- show improved activity against P. aeruginosa . azide ion with relatively low gram-negative activity. (iii) aromatic thiols of 3-acetoxy group results in an enhancement of activity against gram-negative bacteria with improved pharmacokinetic properties. (iv) Replacement of acetoxy group at C-3 position with — CH3, Cl has resulted in orally active compounds.

102. 16 β- LACTAM ANTIBIOTICS (CO-1.1) SAR of cephalosporins 3. Introduction of C-7 α- methoxy group shows higher resistance to hydrolysis by β-lactamases 4. Oxidation of ring sulphur to sulphoxide or sulphone greatly diminishes or destroys the antibacterial activity . 5. Replacement of sulphur with oxygen leads to oxacepam with increased antibacterial activity , with methylene group - greater chemical stability and a longer half-life. 6. The carboxyl group of position-4 has been converted into ester prodrugs to increase bioavailability of cephalosporins , and these can be given orally as well. Examples include cefuroxime axetil and cefodoxime proxetil . 7. Olefinic linkage at C 3-4 is essential for antibacterial activity . Isomerization of the double bond to 2-3 position leads to great losses in antibacterial activity

103. 16 β- LACTAM ANTIBIOTICS (CO-1.1) Nomenclature of cephalosporins The chemical nomenclature of the cephalosporins is slightly more complex than even that of the penicillins because of the presence of a double bond in the dihydrothiazine ring. The fused ring system is designated by Chemical Abstracts as 5-thia-1-azabicyclo[4.2.0]oct-2-ene. In this system, cephalothin is 3-( acetoxymethyl )-7-[2- ( thienylacetyl )amino]-8-oxo-5-thia-1- azabicyclo [4.2.0]oct-2-ene-2-carboxylic acid.

104. 16 β- LACTAM ANTIBIOTICS (CO-1.1) Monobactams Monobactams  are monocyclic and bacterially-produced β- lactam antibiotics. The β- lactam ring is not fused to another ring, in contrast to most other β- lactams .  Monobactams  are effective only against aerobic Gram-negative bacteria (e.g., Neisseria , Pseudomonas)

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106. 16 ANTIBIOTICS (CO-1.1) Monobactams They are resistant to β- lactamases and active against aerobic gram-negative rods . They have no activity against gram-positive bacteria or anaerobes. Aztreonam is the only commercially available monobactam . It is administered either IV or IM and can accumulate in patients with renal failure. Relatively nontoxic, but it may cause phlebitis, skin rash, and, occasionally, abnormal liver function tests. Penicillin-allergic patients tolerate aztreonam without reaction. Monobactams have monocyclic beta lactam ring and are resistant to beta lactamse

107. Aminoglycosides Aminoglycosides  are a class of antibiotics used to treat serious infections caused by bacteria that either multiply very quickly or are difficult to treat.  Aminoglycosides  are called bactericidal antibiotics because they kill bacteria directly. 16 ANTIBIOTICS (CO-1.1)

108. Aminoglycosides Aminoglycosides display concentration-dependent bactericidal activity against "most gram-negative aerobic and facultative anaerobic bacilli" but not against gram-negative anaerobes and most gram-positive bacteria. They require only short contact time and are most effective against susceptible bacterial populations that are rapidly multiplying. 16 ANTIBIOTICS (CO-1.1)

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110. SAR OF AMINIGLYCOSIDE 16 ANTIBIOTICS (CO-1)

111. SAR OF AMINIGLYCOSIDE 16 ANTIBIOTICS (CO-1) 6 amino group increses the activity 6 amino group replace by OH decreases the activity 2 amino group increses the activity 1 2 Acetylating retain the activity

112. SAR OF AMINIGLYCOSIDE 16 ANTIBIOTICS (CO-1.1) 1 2

113. 16 ANTIBIOTICS (CO-1.1) AMINOGYCOSIDE AMINO + GYCOSIDE Polybasic amino groups linked glycosidically to two or more aminosugar .

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115. Amino Glycoside MOA 16 ANTIBIOTICS (CO-1.1)

116. Amino Glycoside MOA 16 ANTIBIOTICS (CO-1.1)

117. Amino Glycoside MOA 16 ANTIBIOTICS (CO-1.3) Aminogycoside are polar so they can not penetrate the peptidoglycan layer Amino glycoside Amino glycoside

118. ANTIBIOTICS (CO-1.3) Aminogycoside are polar so they can not penetrate the peptidoglycan layer Amino glycoside Amino glycoside

119. Streptomycin Streptomycin  is an antibiotic medication used to treat a number of bacterial infections Streptomycin was discovered in 1943 by Albert Schatz from  Streptomyces griseus . It is on the World Health Organization's List of Essential Medicines. 16 ANTIBIOTICS (CO-1.1)

120. Streptomycin 5/1/2024 Chandana majee BP-601T Med.Chem-III Unit-1 16 ANTIBIOTICS (CO-1.3) N Methyl –L-glucosamine L - sterptose S treptidine

121. Streptomycin Streptomycin  is an antibiotic medication used to treat a number of bacterial infections Streptomycin was discovered in 1943 by Albert Schatz from  Streptomyces griseus . It is on the World Health Organization's List of Essential Medicines. 16 ANTIBIOTICS (CO-1.1)

122. Streptomycin Streptomycin, like other aminoglycosidic antibiotics (e.g., gentamycin , neomycin, kanamycin , tobramycin ), inhibits protein synthesis in bacterial cells by binding to the 30S subunit of ribosomes . By doing so, the streptomycin causes a structural change which interferes with the recognition site of codon-anticodon interaction resulting in misreading of the genetic message carried by messenger RNA (mRNA). The mechanism of inhibition of protein synthesis by streptomycin is schematically shown in 16 ANTIBIOTICS (CO-1.1)

123. Streptomycin MOA 16 ANTIBIOTICS (CO-1.1)

124. Streptomycin Infective endocarditis caused by enterococcus when the organism is not sensitive to gentamicin Tuberculosis in combination with other antibiotics. For active tuberculosis it is often given together with isoniazid , rifampicin , and pyrazinamide . It may be useful in cases where resistance to other drugs is identified. Plague ( Yersinia pestis ) has historically been treated with it as the first-line treatment. However streptomycin is approved for this purpose only by the U.S. Food and Drug Administration. • In veterinary medicine, streptomycin is the first-line antibiotic for use against gram negative bacteria in large animals (horses, cattle, sheep, etc.). It is commonly combined with procaine penicillin for intramuscular injection. • Tularemia infections have been treated mostly with streptomycin. 16 ANTIBIOTICS (CO-1.1)

125. Neomycine Neomycin was discovered in 1949 by the microbiologist Selman Waksman and his student Hubert Lechevalier at Rutgers University. It is produced naturally by the bacterium  Streptomyces fradiae Neomycin  is an  aminoglycoside  antibiotic that displays bactericidal activity against gram-negative aerobic bacilli and some anaerobic bacilli where resistance has not yet arisen. It is generally not effective against gram-positive bacilli and anaerobic gram-negative bacilli. Neomycin comes in oral and topical formulations, including creams, ointments, and eyedrops . Neomycin belongs to the  aminoglycosid  class of antibiotics that contain two or more amino sugars connected by  glycosidic bonds 16 ANTIBIOTICS (CO-1)

126. Neomycine S imilar to other aminoglycosides , neomycin has excellent activity against gram-negative bacteria and is partially effective against gram-positive bacteria. It is relatively toxic to humans, with allergic reactions noted as a common adverse reaction (see: hypersensitivity). Physicians sometimes recommend using antibiotic ointments without neomycin, such as  Polysporin . The following represents minimum inhibitor concentration (MIC) susceptibility data for a few medically significant gram-negative bacteria. s Enterobacter cloacae: >16 μg /ml Escherichia coli: 1 μg /ml Proteus vulgaris : 0.25 μg /ml 16 ANTIBIOTICS (CO-1.1)

127. Neomycine In 2005–06, Neomycin was the fifth-most-prevalent allergen in patch test results (10.0%). It is also a known GABA  gamma - Aminobutyric acid antagonist and can be responsible for seizures and psychosis. Like other aminoglycosides , neomycin has been shown to be  ototoxic , causing tinnitus, hearing loss, and vestibular problems in a small number of patients. Patients with existing tinnitus or sensorineural hearing loss are advised to speak with a healthcare practitioner about the risks and side effects prior to taking this medicatio 16 ANTIBIOTICS (CO-1.1)

128. Neomycine Neomycin is typically applied as a topical preparation, such as Neosporin (neomycin/ polymyxin B/ bacitraci ). The antibiotic can also be administered orally, in which case it is usually combined with other antibiotics. Neomycin is not absorbed from the gastrointestinal tract and has been used as a preventive measure for hepatic encephalopath  and  hypercholesterolemi . By killing bacteria in the intestinal tract, Neomycin keeps ammonia levels low and prevents hepatic encephalopathy, especially before gastrointestinal surgery. 16 ANTIBIOTICS (CO-1)

129. 16 ANTIBIOTICS (CO-1.2)

130. Kanamycin Kanamycin A , often referred to simply as  kanamycin , is an antibiotic used to treat severe bacterial infections and tuberculosis. It is not a first line treatment. It is used by mouth, injection into a vein, or injection into a muscle.  Kanamycin is recommended for short-term use only, usually from 7 to 10 days. As with most antibiotics, it is ineffective in viral infections. Common side effects include hearing and balance problems. Kidney problems may also occur.  Kanamycin is not recommended during pregnancy as it may harm the baby. It is likely safe during breastfeeding.  Kanamycin is in the  aminoglycoside  family of medications. It works by blocking the production of proteins that are required for bacterial survival 16 ANTIBIOTICS (CO-1)

131. Kanamycin Spectrum of activity Kanamycin is indicated for short-term treatment of bacterial infections caused by one or more of the following pathogens:  E. coli ,  Proteus  species (both indole -positive and indole -negative),  Enterobacter aerogene ,  Klebsiella pneumoniae ,  Serratia marcescens , and  Acinetobacter  species. In cases of serious infection when the causative organism is unknown, Kanamycin injection in conjunction with a penicillin- or cephalosporin-type drug may be given initially before obtaining results of susceptibility testing. Kanamycin does not treat viral infections 16 ANTIBIOTICS (CO-1.1)

132. Tetracyclines Tetracyclines  are a group of broad-spectrum antibiotic compounds that have a common basic structure and are either isolated directly from several species of  Streptomyces bacteria  or produced semi-synthetically from those isolated compounds.Tetracycline molecules comprise a linear fused tetracyclic nucleus (rings designated A, B, C and D) to which a variety of functional groups are attached.Tetracyclines are named for their four ("tetra-") hydrocarbon rings ("- cycl -") derivation ("- ine "). They are defined as a subclass of  polyketides , having an octahydrotetracene-2-carboxamide skeleton and are known as derivatives of polycyclic naphthacene carboxamide.While all tetracyclines have a common structure, they differ from each other by the presence of chloride, methyl, and hydroxyl groups. 16 ANTIBIOTICS (CO-1.1)

133. Tetracycline Tetracyclines are growth inhibitors ( bacteriostatic ) rather than killers of the infectious agent ( bacteriocidal ) and are only effective against multiplying microorganisms. They are short-acting and passively diffuse through  porin channels in the bacterial membrane. They inhibit protein synthesis by binding reversibly to the bacterial 30S ribosomal subunit and preventing the  aminoacy tRNA  from binding to the A site of the ribosome. They also bind to some extent the bacterial 50S ribosomal subunit and may alter the  cytoplasmic membrane causing intracellular components to leak from bacterial cells. 16 ANTIBIOTICS (CO-1.1)

134. TETRACYCLINE MODE OF ACTION Tetracycline antibiotics are protein synthesis inhibitors. They inhibit the initiation of translation in variety of ways by binding to the 30S ribosomal subunit, which is made up of 16S rRNA and 21 proteins. They inhibit the binding of  aminoacyl-tRNA  to the mRNA translation complex. Some studies have shown that tetracyclines may bind to both 16S and 23S rRNAs.Tetracyclines also have been found to inhibit matrix metalloproteinases . This mechanism does not add to their antibiotic effects, but has led to extensive research on chemically modified tetracyclines or CMTs (like  incyclinide ) for the treatment of  rosacea , acne, diabetes and various types of  neoplasms . 5/1/2024 Chandana majee BP-601T Med.Chem -III Unit-1 16 ANTIBIOTICS (CO-1.1)

135. 5/1/2024 Chandana majee BP-601T Med.Chem -III Unit-1 16 ANTIBIOTICS (CO-1.1)

136. 16 ANTIBIOTICS (CO-1.2)

137. ANTIBIOTICS (CO-1.1)

138. OXYTERTACYCLINE Oxytetracycline  is a tetracycline used for treatment of infections caused by a variety of Gram positive and Gram negative microorganisms including Mycoplasma pneumoniae , Pasteurella pestis , Escherichia coli, Haemophilus influenzae (respiratory infections), and Diplococcus pneumoniae . ANTIBIOTICS (CO-1.1)

139. OXYTERTACYCLINE USES Oxytetracycline , like other tetracyclines , is used to treat many infections, both common and rare (see Tetracycline antibiotics group). Its better absorption profile makes it preferable to tetracycline for moderately severe acne at a dosage of 250–500 mg four times a day for usually six to eight weeks at a time, but alternatives should be sought if no improvement occurs by three months. Oxytetracycline is used to treat infections of the respiratory and urinary tracts, skin, ear, eye and  gonorrhoea although its use for such purposes has declined in recent years due to large increases in bacterial resistance to this class of drugs. The drug is particularly useful when penicillins and/or macrolides cannot be used due to allergy. ANTIBIOTICS (CO-1.1)

140. OXYTERTACYCLINE SIDE EFFECTS Side effects are mainly gastrointestinal and photosensitive allergic reactions common to the tetracycline antibiotic group. It can also damage calcium-rich organs, such as teeth and bones, although this is very rare. It sometimes causes nasal cavities to erode; quite commonly, the BNF suggests, because of this, tetracyclines should not be used to treat pregnant or lactating women and children under 12 except in certain conditions where it has been approved by a specialist because there are no obvious substitutes.  Candidiasis  (thrush) is not uncommon following treatment with broad-spectrum antibiotics. 16 ANTIBIOTICS (CO-1.1)

141. Chlortetracycline Chlortetracycline is a  tetracycline  antibiotic, and historically the first member of this class to be identified. It was discovered in 1945 by the scientist, Benjamin Minge Duggar , working at Lederle Laboratories under the supervision of Yellapragada Subbarow . He discovered that this antibiotic was the product of an actinomycete strain he cultured and obtained from a soil sample from a field in Missouri. The organism was named  Streptomyces aureofaciens  due to its gold-hued color. 16 ANTIBIOTICS (CO-1.1)

142. Chlortetracycline ANTIBIOTICS (CO-1.1)

143. Chlortetracycline Mechanism of action Chlortetracycline , like other tetracyclines , competes for the A site of the bacterial ribosome . This binding competes with tRNA carrying amino acids preven ting the addition of more amino acids to the peptide chain. This inhibition of protein synthesis ultimately inhibits growth and reproduction of the bacterial cell as necessary proteins cannot be synthesized. Chortetracycline reaches peak plasma concentation in about 3 hours . Its oral bioavailability is 25-30%. 16 ANTIBIOTICS (CO-1.1)

144. Chlortetracycline Mechanism of action Chlortetracycline , like other tetracyclines , competes for the A site of the bacterial ribosome . This binding competes with tRNA carrying amino acids preven ting the addition of more amino acids to the peptide chain. This inhibition of protein synthesis ultimately inhibits growth and reproduction of the bacterial cell as necessary proteins cannot be synthesized. Chortetracycline reaches peak plasma concentation in about 3 hours . Its oral bioavailability is 25-30%. ANTIBIOTICS (CO-1.1)

145. Minocycline Minocycline , sold under the brand name  Minocin  among others, is a tetracycline antibiotic used to treat a number of bacterial infections such as pneumonia. It is generally less preferred than the tetracycline  doxycycline . It is also used for the treatment of acne and rheumatoid arthritis. It is taken by mouth or applied to the skin. Common side effects include nausea, diarrhea, dizziness, allergic reactions, and kidney problems. Serious side effects may include anaphylaxis, a lupus-like syndrome, and  eas sunburning  Use in the later part of pregnancy may harm the baby and safety during breastfeeding is unclear. It works by decreasing a bacterium's ability to make protein thus stopping its growth. Minocycline was patented in 1961 and came into commercial use in 1971. It is available as a generic medication. In 2017, it was the 237th most commonly prescribed medication in the United States, with more than two million prescriptions 16 ANTIBIOTICS (CO-1.1)

146. 16 ANTIBIOTICS (CO-1.1)

147. Minocycline Minocycline , sold under the brand name  Minocin  among others, is a tetracycline antibiotic used to treat a number of bacterial infections such as pneumonia. It is generally less preferred than the tetracycline  doxycycline . It is also used for the treatment of acne and rheumatoid arthritis. It is taken by mouth or applied to the skin. Common side effects include nausea, diarrhea, dizziness, allergic reactions, and kidney problems. Serious side effects may include anaphylaxis, a lupus-like syndrome, and  eas sunburning  Use in the later part of pregnancy may harm the baby and safety during breastfeeding is unclear. It works by decreasing a bacterium's ability to make protein thus stopping its growth. Minocycline was patented in 1961 and came into commercial use in 1971. It is available as a generic medication. In 2017, it was the 237th most commonly prescribed medication in the United States, with more than two million prescriptions 16 ANTIBIOTICS (CO-1.1)

148. Minocycline MOA   Protein synthesis inhibitors.They inhibit the initiation of translation in variety of ways by binding to the 30S ribosomal subunit, which is made up of 16S rRNA and 21 proteins. They inhibit the binding of  aminoacyl-tRNA  to the mRNA translation complex.  . It has been shown that tetracyclines are not only active against broad spectrum of bacteria, but also against viruses, protozoa that lack mitochondria and some noninfectious conditions. The binding of tetracyclines to cellular dsRNA (double stranded RNA) may be an explanation for their wide range of effect. It can also be attributed to the nature of ribosomal protein synthesis pathways among bacteria.  Incyclinide was announced to be ineffective for rosacea in September 2007.  16 ANTIBIOTICS (CO-1.1)