General overview on Antibiotic

1. Anti bacterial Agents
By
Pharm BAHATI Abdallah

2. 1. Cell wall synthesis inhibitors
• Target: block peptidoglycan (murein) synthesis
• β-lactam, Vancomycin and Bacitracin
Peptidoglycan
Polysaccharide (repeating disaccharides of
Nacetylglucosamine and N-acetylmuramic acid) + cross-linked
pentapeptide
Peptide cross-link formed between the free amine of the amino
acid in the 3rd position of the peptide & the D-alanine in the
4th position of another chain

3. Α. β-lactam antibiotics
• inhibit transpeptidation reaction to block peptidoglycan synthesis
→involves loss of a D-alanine from the pentapeptide.
Steps:
a. binding of drug to Penicillin Binding Proteins (PBPs)
b. activation of autolytic enzymes (murein hydrolases) in the cell
wall
c. degradation of peptidoglycan
d. lysis of bacterial cell

4. Α. β-lactam antibiotics
i. PENICILLINS
Source: Penicillium spp (molds)
inhibit final cross-linking step
bind to active site of the transpeptidase & inhibit its activity
bactericidal but kills only when bacteria are actively growing
inactivated by β-lactamases

5. i. PENICILLIN
Administered by both Oral and in Systemic circulation (IV, IM etc)
Have wide therapeutic window
Narrow spectrum: Older penicillins like Pen G, Pen V, Ampicillin
which are sensitive mostly in Gram + bacteria.
Broad spectrum: The semisynthetic Penicillins like Amoxycillin
and the Penicillinase resistant drugs (eg Oxacillin and Nafcillin)
Common side effect is Allergy (Steven Johnson Syndrome)
Rash, Swelling, Itching

6. Α. β-lactam antibiotics
ii. CEPHALOSPORIN
similar structure, pharmacokinetics and mechanism of action as
penicillin and side effects.
most are products of molds of the genus Cephalosporium
 Used mostly in Surgical Prophylaxis, Otitis media, URIs
4 generations (Assignment)

7. B. Other β-lactam antibiotics
CARBAPENEMS
structurally different from penicillin and cephalosporin
Imipenem and Meropenem
widest spectrum of activity of the β-lactam drugs
Bactericidal vs. many gram (+), gram (-) and anaerobic bacteria
not inactivated by β-lactamases

8. B. Other β-lactam antibiotics
MONOBACTAMS (Aztreonam)
activity vs. gram negative rods
useful in patients hypersensitive to penicillin

9. C. Other Cell Wall Inhibitors
VANCOMYCIN
Source: Streptomyces orientalis
Must monitor bioavailable conc, due to oto and nephron toxicity
Inhibit 2nd stage of peptidoglycan synthesis by:
a. binding directly to D-alanyl-D-alanine block transpeptidase
binding
b. inhibiting bacterial transglycosylase
Eg. S. aureus & S. epidermidis infection resistant to penicillinase-
resistant PEN

10. C. Other Cell Wall Inhibitors
BACITRACIN
Source: Bacillus licheniformis
Prevent dephosphorylation of the phospholipid that carries the
peptidoglycan subunit across the membrane →block regeneration
of the lipid carrier & inhibit cell wall synthesis
Too toxic for systemic use and hence, they are used in treatment of
superficial skin infections

11. 2. Inhibition of cell membrane function
• They work by altering the permeability of the cell
membrane of a microorganism
• Eg Polymyxins, Polyene and Azoles (Imidazole)

12. A. POLYMYXINS
Source: Bacillus polymyxa
With positively charged free amino group →act like a cationic
detergent → interact with lipopolysaccharides & phospholipid in
outer membrane → increased cell permeability
Activity: gram negative rods, especially Pseudomonas
aeruginosa
Examples are Polymyxin B (colistin) and E
They are used as a last choice when other drugs are ineffective or
contraindicated because the cause neuro and nephro toxicity.

13. B. POLYENE (Antifungal)
• Require binding to a sterol (ergosterol) →change permeability
of fungal cell membrane
AMPHOTERICIN B
Preferentially binds to ergosterol
With series of 7 unsaturated double bonds in macrolide ring
structure
Activity: disseminated mycoses
NYSTATIN
Structural analogue of amphotericin B
Topical vs. Candida

14. C. Azoles
• Block cytP450-dependent demethylation of lanosterol
→inhibit ergosterol synthesis
• Eg Ketoconazole, Fluconazole, Itraconazole, Miconazole,
Clotrimazole

15. 3. Inhibition of nucleic acid synthesis
• They work by either inhibiting synthesis pathway for
metabolites for nucleic acid or by direct inhibiting DNA
synthesis.
• Eg Inhibition of precursor synthesis (sulfamethoxazole
and Trimethoprim) and Inhibition of DNA synthesis
(Quinolones and Metronidazole)

16. A. Inhibition of precursor synthesis
Inhibit synthesis of essential metabolites for synthesis of
nucleic acid
SULFONAMIDES
Structure analogue of PABA (precursor of tetrahydrofolate)→inhibit
tetrahydrofolate → methyl donor in synthesis of A, G and T
Bacteriostatic vs. bacterial diseases (UTI, otitis media secondary to S.
pneumoniae or H. influenzae, Shigellosis, etc.)
DOC for Toxoplasmosis & Pneumocystis pneumonia
Causes Anaemia, Thrombocytopenia, Photosensitivity and Urticaria

17. A. Inhibition of precursor synthesis
TRIMETHOPRIM
Inhibit dihydrofolate reductase (reduce dihydrofolic to
tetrahydrofolic acid) →inhibit purine synthesis
TRIMETHOPRIM + SULFAMETHOXAZOLE
Produce sequential blocking →marked synergism of activity
 Bacterial mutants resistant to one drug will be inhibited by the
other

18. B. Inhibition of DNA synthesis
QUINOLONES
oInhibit DNA gyrase in susceptible organism and promotes
breakage of double-stranded DNA
oBactericidal; not recommended for children & pregnant women
since damages growing cartilage
oExcellent oral absorption
oInterfere with mineral containing drugs (antiacid) and food in
absorption
oFluoroquinolones (Ciprofloxacin), Norfloxacin, Ofloxacin, etc.

19. B. Inhibition of DNA synthesis
METRONIDAZOLE
Anti-protozoal; anaerobic infections
Antimicrobial property due to reduction of its nitro group by
bacterial nitroreductase → (+) production of cytotoxic compounds
→ disrupt bacterial DNA
Causes GI upsets, may darken the urine
Contraindicated with alcohol

20. 4. Inhibition of protein synthesis
They mainly inhibit translation and transcription
processes of protein synthesis.
Binds the ribosomes result in:
1. Failure to initiate protein synthesis
2. No elongation of protein
3. Misreading of tRNA-deformed protein

21. A. Drugs that act on the 30S subunit
AMINOGLYCOSIDES (Streptomycin)
Mechanism of bacterial killing involves the following steps:
1. Attachment to a specific receptor protein (e.g. P 12 for
Streptomycin)
2. Blockage of activity of initiation complex of peptide formation
(mRNA + formylmethionine + tRNA)
3. Misreading of mRNA on recognition region → wrong amino acid
inserted into the peptide

22. AMINOGLYCOSIDES (Streptomycin)
They have poor absorption rate hence being administered direct
to the systemic circulation.
Causes
-Ototoxicity and Nephrotoxicity
-Increased thirst
-Skin rash and Itchiness

23. A. Drugs that act on the 30S subunit
TETRACYCLINES
Source: Streptomyces rimosus
Bacteriostatic vs. gram (+) and gram (-) bacteria, mycoplasmas,
Chlamydiae & Rickettsiae
Block the aminoacyl transfer RNA from entering the acceptor site
prevent introduction of new amino acid to nascent peptide chain

24. TETRACYCLINES
Given commonly by oral route but with an empty stomach.
Its absorption is altered by mineral drugs or food (milk)
Contraindicated for children and pregnant and breast feeding
mothers
Causes GI upsets, swollen tongue, black or hairy tongue,
vaginal itching, and white patches or sores in the mouth or
lips.

25. B. Drugs that act on the 50S subunit
CHLORAMPHENICOL
• Inhibit peptidyltransferase → prevent synthesis of new peptide
bonds.
• Mainly bacteriostatic; used commonly for treatment of
complicated typhoid fever.
• Given orally and IV route
• Causes Headache, GI upsets, Altered mental status (confusion)
• It is not commonly used nowdays because of its resistance caused
by drug efflux and chloramphenicol acetyltransferase.

26. B. Drugs that act on the 50S subunit
MACROLIDES (Erythromycin, Azithromycin &
Clarithromycin)
Binding site: 23S rRNA
Mechanism:
1. Interfere with formation of initiation complexes for peptide
chain synthesis
2. Interfere with aminoacyl translocation reactions → prevent
release of uncharged tRNA from donor site after peptide bond is
formed (Erythromycin)

27. • MACROLIDES (Erythromycin, Azithromycin &
Clarithromycin)
• Taken mainly by oral route
• Erythromycin causes abdominal pain when taken before meal
• Causes GI upsets, tinnitus, cholestatic hepatitis (mainly by
erythromycin)
• Their resistance is due ribosomal mutations

28. B. Drugs that act on the 50S subunit
LINCOSAMIDES (Clindamycin)
Source: Streptomyces lincolnensis
• resembles macrolides in binding site, antibacterial activity and
mode of action
• Bacteriostatic vs. anaerobes, gram + bacteria (C. perfringens) and
gram – bacteria (Bacteroides fragilis)

29. • LINCOSAMIDES (Clindamycin)
• Topical, Oral and Injectable routes
• Same pharmacokinetics as macrolides
• Causes GI upset, Joint pain, Heartburn and Sore throats
• Rarely side effect but need medical attention: Jaundice (eye and
skin), Dark urine, and change in the amount of urine

30. C. Drugs that act on both the 30S and 50S
subunit
GENTAMICIN
Treatment of systemic infections by susceptible gram (-) bacteria
including Enterobacteriaceae & Pseudomonas
AMIKACIN
Treatment of infection by gram (-) bacteria resistant to other
aminoglycosides
KANAMYCIN
Broad activity vs. gram (-) bacteria except Pseudomonas

31. END