Tri Widyawat & Sit Syarifah

Dep. Farmakologi & Terapeutik,

Fakultas Kedokteran
Universitas Sumatera Utara
The tree of antbiotcs
Bacterial Targets for Antbiotcs
 Inhibitors of Cell wall synthesis
bactericidal, time dependent killing
1. Beta-lactams (penicillins,
cephalosporins, carbapenems,
monobactams)
2. Cycloserine
3. Glycopeptides (vancomycin,
teicoplanin)
4. Bacitracin
 Cell Wall Actve Agents
• B-lactams bind to “penicillin binding proteins” (PBP)
-PBP are essential enzymes involved in cell wall
synthesis
-weakened / distorted cell wall leading to cell lysis
and death

• Glycopeptdes bind to the terminal D-ala of nascent

cell wall peptides and prevents cross-linking of these
peptide to form mature peptidoglycan
 Bacterial cytoplasmic membrane

Structural Features of Bacteria 6

 Synthesis of peptdoglycan

Structural Features of Bacteria 7

 Antbiotcs that inhibit PG synthesis
• Fosfomycin (Monurol) – inhibits formation of PG
subunit

• Bacitracin – binds lipid carrier, inhibits externalization

of PG subunit (toxic, usually used topically)

• Penicillins and cephalosporins (-lactam antibiotics) -

inhibits PG crosslinking

• Vancomycin (glycopeptide antibiotics; Vancocin) –

inhibits PG crosslinking

Structural Features of Bacteria 8

Structure of -lactam drugs

Penicillins e.g.,
penicillin, cloxacillin,
flucloxacillin, ampicillin, amoxycillin,
carbenicillin, ticarcillin, azlocillin,
mezlocillin, piperacillin

Cephalosporins e.g.,
cephalexin, cefaclor,
cefadrxil, cefuroxime,
cefamandole, cefotaxime,
ceftazidime, cetriaxone, cefixime
 Penicillins
• Penicillin G / V
- good gram positive (not Staph)
-moderate anaerobic activity
• Synthetc penicillins (Ampicillin)
- good gram positive (not Staph)
- moderate gram negative (not Pseudomonas)
• Ant-staphylococcal penicillins
- Cloxacillin
• Ant-pseudomonal penicillins
- Piperacillin
 PENICILLIN
• First antibiotic
• Active for coccus gram negative and positive
• Side effects  allergy, anaphylactic shock,
toxic reaction, and local irritation.
• Excreted by urine
• High resistancy rate
 Actvity of ß-lactams against common organisms
Gram (+)ve Gram (-)ve
Staphylo Strepto Entero Pseudo
Penicillins cocci cocci cocci E.coli monas
Benzylpenicillin + + R R R
Flucloxacillin + + R R R
Amoxycillin + + + + R
Piperacillin + + + + +

Cephalosporins
Cephalexin + + R Urine only R
Cefuroxime + + R + R
Ceftriaxone R + R + R
Ceftazidime R + R + +

Carbapenems
Imipenem + + + + +
 CEPHALOSPORINS
• Produced by Cephalosporium acremonium
• Inhibit the 3rd step transpeptidase reaction in microbial membrane
synthesis.
Type of Cephalosporin :
 1st Generation (Cefadroxil, Cefazolin, Cephalexin, etc)
 2nd Generation (Cefaclor, Cefoxitin, Loracarbef, etc)
 3rd Generation (Cefixime, Cefoperazone, Cefotaxime, Ceftazidime,
Ceftriaxone, etc)
 4th Generation (Cefepime)
Administration : Oral, Intravenous, Intramuscular.
• Cross the placental and blood brain barrier.
• Excretion : kidney and bile.
• Side Effects : Allergic reaction, anaphylactic reaction with bronchospasme
and urticaria, diarrhea, bleeding, etc.
 Cephalosporines
Generation Examples Activity
First Generation cefazoline mainly gram pos,
Cefadroxil some gram neg
Cephalexin
Second Cefaclor weaker gram pos, More expensive
Generation Cefprozil better gram neg Absorption with food:
Ceclor – Decreased
Cefuroxime axetil Cefzil -- No effect
Ceftin -- Increased

Third Generation Cefdinir excellent gram Convenient

Cefixine neg, dosage-once or
Cefpodoxine some gram pos twice daily
Ceftriaxone
Fourth generation Cefepime excellent gram
neg,
good gram pos
 Vancomycin: Mechanism of Acton

• Inhibit peptidoglycan synthesis in bacterial cell wall by

complexing with the D-alanyl-D-alanyl portion of the cell wall
precurser
carboxypeptidase
-L-ala-D-glu-L-lys-D-ala-D-ala
2L-ala
racemase
transpeptidase
2D-ala
-L-ala-D-glu-L-lys-D-ala-D-ala
ligase (ddl)
D-ala-D-ala -L-ala-D-glu-L-lys-D-ala-D-ala
transglycosidase
UDP-L-ala-D-glu-L-lysadding enzyme -L-ala-D-glu-L-lys-D-ala-D-ala

UDP-L-ala-D-glu-L-lys-D-ala-D-ala
--L-ala-D-glu-L-lys-
-D-ala-D-ala
pentapeptide--

vancomycin
 Cell Wall Actve Agents
• B-lactam resistance
1. Production of a B-lactamase (most common)
2. Altered PBP (S.pneumoniae)
3. Novel PBP (MRSA)
4. Altered permeability

• Glycopeptde resistance
- primary concern is Enterococcus / S.aureus
- altered target
- bacteria substitutes D-lac for D-ala
- vancomycin can no longer bind
 Beta-lactamase inhibitors
• Clavulanic acid:
- used with amoxycillin (Augmentin®,
Amoxyclav ®)
- used with ticarcillin (Timentin®)
• Sulbactam:
- used with ampicillin (unavailable in UK)
• Tazobactam
- used with piperacillin (Tazocin®)
 Inhibitors of protein synthesis
• Ribosomes are the site of protein synthesis
• many classes of antibiotics inhibit protein
synthesis by binding to the ribosome
• binding may be reversible or irreversible
1.Aminoglycosides
2.Macrolides
3.Tetracyclines
4.Chloramphenicol
5.Fusidic acid
Macrolides
 Aminoglycosides - general propertes

• Major weapon in treatment of severe sepsis

– Gram negative, rapid bactericidal effect
• Fat insoluble and not absorbed orally
– Effective by the parenteral route
• Entry into cells depends upon oxygen-dependent
transport (lacked by streptococci & enterococci)
• Toxic to the kidney and inner ear - imperative to
measure levels
 Aminoglycosides
Aminoglycoside Comment
Gentamicin First broad spectrum
aminoglycoside
Tobramycin Similar spectrum to gentamicin
Amikacin Semi-synthetic derivative of
kanamycin, active against
Gentamicin-resistant G(-)ve
rods
Neomycin Toxic- used topically
Streptomycin Oldest aminoglycoside –
now used to treat TB
 Aminoglycosides - spectrum of actvity
Gram (+)ve Gram (-)ve
Staphylo Strepto Entero Pseudo
Drug cocci cocci cocci E.coli Klebsiella monas
Gentamicin + + + + + +
Amikacin + + + + + +
Streptomycin + + + + + +

Gram (+)ve wall

structure (stain with
difficulty)
Entero- Bacter-
M. tb MAI bacter Proteus oides
Gentamicin R + + + R
Amikacin + + + + R
Streptomycin + + + + R
 Macrolides
• Erythromycin
CH3
• Azithromycin
O
• Clarithromycin
H3C OH
CH3
HO
O OH N(CH3)
Large structures:
HO O CH3
H3C
14- (Erythromycin & CH3
H5C2
Clarithromycin), O
CH3 O
15- (Azithromycin), OCH3

or 16-membered O O OH
CH3
rings.
 Macrolides - general propertes

• Newer macrolides inhibit Mycobacteria,

protozoa (T. gondii, E. histolytica, P.
falciparum), Campylobacter, Helicobacter,
Borrelia, Neisseria & other genital pathogens
• GI complications, mostly with erythromycin
• Given orally, but absorbtion & bioavailability
variable from one macrolide to another
 Macrolides
• Erythromycin is inactivated by gastric acid.
• Erythromycin esters are less susceptible to acid
inactivation and are better absorbed
• It inhibits cytochrome P 450
• Erythromycin and Azithromycin are excreted in
bile.
• Clarithromycin appear in urine and bile.
• Azithromycin has large Vd – high tissue
distribution – concentrated in neutrophils,
macrophages.
 Pharmacokinetc of Macrolides

MACRO- Oral Cytochrome Spectrum Half life

LIDES absorption P450 (hours)
Erythro- yes Inhibits Penicillin 2
mycin
Clarithro- Stable to Inhibits MAC My, 4
mycin acid HP, C,Leg
Azithro- Stable to No H.Inf, Chl >40
mycin acid MAC
Telithro- Stable to Inhibits Same as 10
mycin acid Azithro
 Macrolides
Adverse effects :
• Epigastric distress - erythromycin
• Cholestatic jaundice (mainly with erythromycin
estolate)
• Ototoxicity – erythromycin at high dose.

Drug - drug interactions

• Erythromycin, Clarithromycin and Telithromycin
inhibit the cytochrome P450 system and so
potentiate the activity of theophylline and
terfenadine
 Clindamycin
Pharmacodynamic
• Active against gram +ve and anaerobes
• Good activity against bacteroides (including B. fragilis) and Penicillin resistant
streptococcus.
• No activity against most gram -ve bacteria
Pharmacokinetic
• Well absorbed orally
• Distribution in most tissues including bone.
• Excretion is mainly biliary and also in urine.
Adverse effects
• Gastrointestinal super-infections – potentially fatal pseudo-membranous colitis
by C. difficile.
• Oral Metronidazole and Vancomycin are used for the treatment of the fatal
pseudo-membranous colitis.
 Linezolid
• the first oxazolidone antbiotc
• Blocks 70S ribosome assembly by binding 50 S
subunit
 Linezolid
Anti-bacterial spectrum :
• Gram positive bacteria only
– Penicillin resistant
streptococci
– Methicillin and Vancomycin
staphylococcus
– Vancomycin resistant
enterococcus
– Lister monocytogenes,
Corynebacterium spp
• Also active against
mycobacteria tuberculosis and
Clostridium
Pharmacokinetics :
• Orally absorbed
• Well distributed
• Excreted by renal and non-
renal routes
Adverse effects :
• Nausea and diarrhea
• Thrombocytopenia
• Inhibits MAO, avoid tyramine
containing foods
 Tetracyclines

R1 R2 R3 R4 Inhibit protein synthesis

OH by preventing amino-acyl
transfer RNA from
CONH2
entering the acceptor
OH
OH O OH O sites on the ribosome

Natural e.g., Semi-synthetic e.g.,

chlortetracycline, doxycycline,
oxytetracycline, minocycline
tetracycline
 Tetracyclines – general propertes
• Active against many common Gram (+)ve & (-)ve
bacteria, chlamydiae, rickettsiae, coxiellae, spirochaetes,
some mycobacteria, E histolytica, & plasmodia
• Adiministration : oral, intravenous, intramuscular
– Given orally, absorption affected by food
• Effect on dentition (chelates Ca)
• Contraindication : pregnancy, lactating, growing child,
liver and renal insufficiency
• Side effects : Allergic, anaphilactic, toxic reaction,
diarrhea (GI intolerance common)
Chloramphenicol - general propertes
H NHCOCHCl2

O2N C C CH2OH

OH H

• Nitrobenzene nucleus - Blocks peptidyl transferase,

thereby blocking peptide bond synthesis
• Bacteriostatic against G(+)ves, many Gram (-)ves (not P.
aeruginosa), leptospires, T. pallidum, chlamydiae,
mycoplasmas, rickettsiae, & many anaerobes, (B. fragilis
less so)
– Bacteriostatic and bactericid ( in high concentration)
• Second line agent due to marrow effects
 Fusidic acid - general propertes
• Active against most Gram (+)ves
and Gram (-)ve cocci, including
MRSA
• Some activity against G. lamblia, P.
COOH
falciparum
H
HO OAc • Some activity against
Mycobacteria
H • Mostly used for staphylococcal
HO
infections (osteomyelitis) and
H
topically
• Well absorbed orally
Inhibitors of Nucleic acid synthesis
• Inhibiton of synthesis of precursors
Sulphonamides
Trimethoprim
• Inhibitors of DNA replicaton
Quinolones
• Inhibitors of RNA polymerase
Rifampicin
Inhibiton of synthesis of precursors
Drugs actng on microbial folate synthesis

• Trimethoprim - inhibits folate

required for the synthesis of purines
and pyrimidines by enzyme inhibition

• Sulphonamides - also inhibit folate

synthesis by enzyme inhibition
 Trimethoprim- Sulfamethoxazole
(TMP-SMX)
• Prepared as a fixed 5:1 ratio of SMX to TMP
• MOA - inhibits two steps in the folic acid pathway
– optimal antibacterial effects occur at a ratio of 1:20 (TMP:SMX)
which is also the peak concentration following oral and IV
administration
• Pharmacokinetics:
– Oral bioavailability > 90%
– Widely distributed into body tissues and fluids
– Metabolized in liver (Acetylated and glucuronide conjugated ) -
then renally excreted
– SMX: 70% in protein bound
• It displaces bilirubin, so it can cause newborn jaundice or make it worse if used in
third trimester.
Mechanism of action of
TMP-SMX
 Sulphonamides - general propertes
• First chemotherapeutic
• Broad spectrum activity
– Restricted in use by resistance
– Side effects  allergy, anaphylactic shock, toxic reaction,
and local irritation.
• Many interactions with other drugs due to plasma
protein binding
• Principal use has been for treatment of UTIs
– Excreted by urine
• Useful in treatment of Nocardia, & Toxoplasma gondii
 Untoward effects of
sulfonamides
• Hematopoietc system:
– Hemolytic anemia (in glucose-6-phosphate dehydrogenase deficient patients);
– aplastic anemia; thrombocytopenia; eosinophylia.
• Urinary tract:
– Occlusions due to precipitates and hypersensitivity reactions.
• Drug interacton:
– Due to the high affinity to plasma proteins.
– These include anticoagulants, hydantoin and hypoglycemic agents of
sulfonylurea group.
• Therefore, the patient must be given sufficient amount of
water to produce 1.2 liter/day of urine (i.e. 3-4 liter of
water/day).
 Inhibitors of DNA replicaton

• Quinolones (eg ciprofloxacin - a

fluoroquinolone) large family of
synthetic agents that affect DNA gyrase
• DNA gyrase required to supercoil
bacterial DNA (it is also important in
DNA repair) – bacteria unable to ‘pack’
DNA into cell
 Quinolones
• These are synthetic anti-microbials.
• The member of this group –
– Old quinolon (unfluorinated quinolone; first
generation)
– Fluoroquinolones
• Bactericidal and concentration dependent.
• Long post-antibiotic effect on
enterobacteriacea
 FLUOROQUINOLONES
• Fluoroquinolones (ciprofloxacin, norfloxacin, levofloxacin, moxifloxacin)
- bactericidal, concentration dependent
- bind to 2 essential enzymes required for DNA
replication
- DNA gyrase and topoisomerase IV
- gram pos and gram neg
- atypical bacteria, some have anaerobic activity
• Farmakokinetic : well absorbed by oral administration
widely distributedExcreted by urine
• Clinical use : UTI, RTI, STD, arthritis, bone infection
• Side effects : Nausea, vomite, headache.
 Fluoroquinolones
Generaton Examples Spectrum
First Nalidixic acid, gram -ve only ;
generation Pipemidic acid U T I
Second Ciprofloxacin, gram –ve, gram +ve,
generation Norfloxacin, atypical like
Ofloxacin mycoplasma and
chlamydia

Third Sparfloxacin, gram –ve, gram +ve

generation Moxifloxacin, S. pneumoniae,
Gatifloxacin atypical, anaerobes
Fourth Trovafloxacin gram +ve and many
generation anaerobes.
Mechanism of acton Quinolones
 Fluoroquinolones
Pharmacokinetcs :
• Orally well absorbed, metabolism in liver
• FQ chelate Ca, Mg, Fe and Zn
• High tissue penetration – bone, lungs and
phagocytes exceeds that in plasma
• Excreted primarily in urine –
(Trovafloxacin and Sparfloxacin are
predominantly eliminated by non – renal
route)
 Fluoroquinolones
Adverse effects :
• CNS : dizziness, confusion, seizures threshold is
decreased.
• Cartlage damage
– Quinolones are not recommended for
prepuberal children and pregnant woman
due to possible arthropathy in children
• Liver failure – Trovafloxacin
• QT prolonged – Sparfloxacin and Moxifloxacin
• Phototoxicity – Sparfloxacin
 Fluoroquinolones
Drug interacton
• Plasma concentrations of theophylline,
Warfarin, Caffeine are increased by FQ due to
inhibition of metabolism of these drugs
• FQ enhance the CNS toxicity of Caffeine and
seizures are reported.
 Inhibitors of RNA polymerase
that affect bacterial DNA and RNA
• Rifamycins (eg rifampacin) specific
inhibitors of bacterial DNA-dependent
RNA polymerase – blocks mRNA
• Metronidazole (a nitroimidazole)
When reduced it can react with DNA,
oxidizing it and causing strand breaks
 METRONIDAZOLE
• Active for the anaerob
• Well oral absorption
• Effect on CNS
• Drug of choice for  paracytic infection (G.
lamblia), amoeba, and bacterial vaginosis.
 Characteristcs of a good antbiotc
• Kills or inhibits the growth of bacteria at low
concentratons
• Broad spectrum
• Minimal side effects
– Due to direct effects of antibiotic itself
– Due to effects on the normal microflora of the body
• Appropriate pharmacokinetc propertes
– Must get to the site of infection in high concentrations
– Distribution influences mode of administration (oral,
injected)

Structural Features of Bacteria 52