Antibiotics and Synthetic Antimicrobial agents

Antibiotics and Synthetic Antimicrobial agents
β-lactam
Spectrum of Activity
Cephalosporins
Clavams
1-oxacephems
1-carbapenems
1-carbacephems
Nocardicins
Monobactams
Penicillanic acid derivatives

1. Antibiotics and Synthetic Antimicrobial agents

2. 2 Chloramphenicol was an early example

3. Antibiotics can be Bacteriostatic or Bactericidal ( static=stop; cidal =kill ) whilst humans (and all other eukaryotes) have 80S ribosomes bacterial cells have 70S ribosomes, with a smaller molecular weight and different shape

4. Definition An antibiotic refers to a substance produced by a microorganism, or to a similar substance (produced wholly or partly by chemical synthesis), which in low concentrations inhibits the growth of other microorganisms. Chloramphenicol was an early example.

5. Sources 1. Microorganisms; Most antibiotics in current use have been produced from Streptomyces spp. 2. Synthesis ; Chloramphenicol is now usually produced by a synthetic process. 3. Semisynthesis ; part of the molecule is produced by a fermentation process the product is then further modified by a chemical process . Many penicillins and cephalosporins are produced in this way. (Streptomyces venezuelae )

6. β- lactam Beta-lactam antibiotics kill bacteria that are surrounded by a cell wall. Bacteria build cell walls by linking molecules together—beta-lactams block this process. Without support from a cell wall, pressure inside the cell becomes too much and the membrane bursts.

7. There are several different types of β -lactam antibiotics that are valuable, or potentially important, antibacterial compounds. penicillin and cephalosporin

8. Penicillins

9. Wonder Drug Dr. Fleming famously wrote about that red-letter date : “When I woke up just after dawn on September 28, 1928 , I certainly didn’t plan to revolutionize all medicine by discovering the world’s first antibiotic, or bacteria killer. But I guess that was exactly what I did.” Dr. Fleming Dr. Howard Florey and Dr. Ernst Chain

10. The penicillins may be considered as being of the following types. Naturally occurring . For example, those produced by fermentation of moulds such as Penicillium notatum and P. chrysogenum . examples are benzylpenicillin ( penicillin G ) and phenoxymethylpenicillin ( penicillin V ). Semisynthetic. Example, Amoxicillin

11. Several bacteria produce an enzyme, Beta-lactamase which may inactivate a penicillin by opening the Beta-lactam ring ,

12. In general, the penicillins are active against Gram-positive bacteria some members (e.g. ampicillin ) are also effective against Gram-negative bacteria though not Pseudomonas aeruginosa whereas others (e.g. carbenicillin ) are active against Pseudomonas aeruginosa also.

13. Spectrum of Activity

14. Cephalosporins 1950s; species of Cephalosporium (now known as Acremonium ) produce the following antibiotics: An acidic antibiotic, cephalosporin P (subsequently found to have a steroid-like structure) Another acidic antibiotic, cephalosporin N (later shown to be a penicillin). Cephalosporin C , obtained during the purification of cephalosporin N; this is a true cephalosporin , and from it has been obtained 7-aminocephalosporanic acid (7-ACA), the starting point for new cephalosporins .

15. dihydrothiazine ring Thiazolidine Ring

16. Cephalosporins disrupt the synthesis of the peptidoglycan layer forming the bacterial cell wall. As a result, the bacteria die. First-generation cephalosporins are active predominantly against Gram-positive bacteria, and successive generations have increased activity against Gram-negative bacteria ( though often with reduced activity against Gram-positive organisms ) They are less susceptible to β-lactamases

17. Antibiotics weaken the cell wall, and cause the cell to lyse.

18. The classification of cephalosporins into "generations"

19. Generation 1 Activity against Gram-positive : Activity against penicillinase-producing, methicillin-susceptible staphylococci and streptococci . No activity against methicillin-resistant staphylococci or enterococci. Activity against Gram-negative : Activity against P roteus mirabilis , some E . c oli , and K lebsiella pneumoniae (" PEcK ") , but have no activity against Bacteroides fragilis , Pseudomonas, Acinetobacter, Enterobacter , indole-positive Proteus , or Serratia

20. Cefadroxil ( cefadroxyl ; Duricef ) Cephalexin ( cefalexin ; Keflex ) Cefalotin ( cephalothin ; Keflin ) Cefapirin ( cephapirin ; Cefadryl ) Cefradine ( cephradine ; Velosef ) Some of the Members of Generation 1

21. Generation 2 Activity against Gram-positive : Less than first-generation. Activity against Gram-negative : Greater than first-generation: HEN Haemophilus influenzae , Enterobacter aerogenes and some Neisseria + the PEcK described before

22. Some of the Members of Generation 2 Cefaclor ( Ceclor , Distaclor , Keflor , Raniclor ) Cefonicid ( Monocid ) Cefprozil ( cefproxil ; Cefzil ) Cefuroxime ( Zefu , Zinnat , Ceftin , Xorimax )

23. Generation 3 Activity against Gram-positive : Some members of this group (in particular, those available in an oral formulation, and those with antipseudomonal activity) have decreased activity against gram-positive organisms. Activity against Gram-negative : Third-generation cephalosporins have a broad spectrum of activity and further increased activity against gram-negative organisms.

24. Some of the Members of Generation 3 Ceftriaxone ( Rocephin ) Cefotaxime ( Claforan ) Ceftazidime ( Fortaz ) (strong antipseudomonal activity)

25. Able to penetrate the central nervous system , making them useful against meningitis caused by pneumococci, meningococci, Haemophilus influenzae , and susceptible E. coli , Klebsiella , and penicillin-resistant Neisseria gonorrhoeae

26. Generation 4 Activity against Gram-positive: They are extended-spectrum agents with similar activity against Gram-positive organisms as first-generation cephalosporins . Activity against Gram-negative: Fourth-generation cephalosporins are zwitterions that can penetrate the outer membrane of Gram-negative bacteria . They also have a greater resistance to β-lactamases than the third-generation cephalosporins . Effective in meningitis .

27. Some of the Members of Generation 4 Cefepime ( Maxipime ) antipseudomonal activity Cefpirome ( Cefrom )

28. Generation 5 has powerful antipseudomonal characteristics and appears to be less susceptible to development of resistance Effective against MRSA (Methicillin-resistant Staphylococcus aureus ) Ceftolozane (super antipseudomonal activity) Ceftaroline (only cephalosporin to treat MRSA) Some of the Members of Generation 5

29. Clavams The clavams differ from penicillins in two respects, namely the replacement of S in the penicillin thiazolidine ring with oxygen in the clavam oxazolidine ring and the absence of the side-chain at position 6.

30. Clavulanic acid Isolated from Streptomyces clavuligerus has poor antibacterial activity potent inhibitor of staphylococcal beta-lactamase and of most types of Beta-lactamases produced by Gram-negative bacteria

31. 1-oxacephems example latamoxef (moxalactam) the sulphur atom in the dihydrothiazine cephalosporin ring system is replaced by oxygen. The introduction of the 7-a-methoxy group (as in cefoxitin), however, stabilizes the molecule. Latamoxef is a broad-spectrum antibiotic with a high degree of stability to most types of Beta-lactamases, and is highly active against the anaerobe, B . fragilis .

32. 1-carbapenems Comprise a new family of fused Beta-lactam antibiotics They are analogues of penicillins or clavams , the sulphur ( penicillins ) or oxygen ( calvams ) atom being replaced by carbon. Examples are the olivanic acids, thienamycin and imipenem

33. 1-carbacephems The sulphur in the six-membered dihydrothiazine ring of the cephalosporins is replaced by carbon. Loracarbef is a new oral carbacephem which is highly active against Gram-positive bacteria, including staphylococci.

34. Nocardicins The nocardicins (A to G) have been isolated from a strain of Nocardia and comprise a novel group of Beta-lactam antibiotics. Nocardicin A is the most active member, and possesses significant activity against Gram-negative but not Gram-positive bacteria.

35. Monobactams The monobactams are monocyclic Beta-lactam antibiotics produced by various strains of bacteria. A novel nucleus , 3-aminomonobactamic acid (3-AMA), has been produced from naturally-occurring monobactams. Several monobactams have been tested and one ( aztreonam ) has been shown to be highly active against most Gram-negative bacteria and to be stable to most types of Beta-lactamases.

36. Assignment Penicillanic acid derivatives

37. Penicillanic acid derivatives Penicillanic acid derivatives are synthetically produced /3-lactamase inhibitors. Penicillanic acid sulphone protects ampicillin from hydrolysis by staphylococcal /^-lactamase and some, but not all, of the ^-lactamases produced by Gram-negative bacteria, but is less potent than clavulanic acid. /3-bromopenicillanic acid inhibits some types of /^-lactamases. Tazobactam is a penicillanic acid sulphone derivative marketed as a combination with piperacillin. Alone it has poor intrinsic antibacterial activity but is comparable to clavulanic acid in inhibiting /J-lactamase activity. Sulbactam is a semisynthetic 6-desaminopenicillin sulphone structurally related to tazobactam . Not only is it an effective inhibitor of many /^-lactamases but it is also active alone against certain Gram-negative bacteria. It is used in combination with ampicillin for clinical use.

38. Hypersensitivity https://goo.gl/xFS1BM