Antimycobacterial agents

Dr. Amal belaid

OUTLINES
 Introduction
 Classifications
Structures
MOA
SAR
(a) The innermost layer of the mycobacterial cell envelope is
composed of peptidoglycan and is lined by a layer of
arabinogalactan. The presence of mycolic acids covalently
bound to arabinogalactan, aswell as the interaction of
glycolipids and lipoglycans with mycolic acids in the outer
layer, confers high hydrophobicity to the mycobacterial cell
wall

(b) Gram-negative cell walls contain a thin peptidoglycan

layer that lines the plasma membrane and an outer
membrane composed of lipopolysaccharides, responsible for
their antigenic properties;

(c) The cell walls of Gram-positive bacteria are thick and

mainly composed of a peptidoglycan layer adjacent to the
 Mycobacteria
• Mycobacteria are intrinsically resistant to most antibiotics.
• Because they grow slowly compared with other bacteria,
antibiotics that are most active against growing cells are
relatively ineffective.
• Mycobacterial cells can also be dormant and thus
completely resistant to many drugs or killed only very
slowly.
• The lipid-rich mycobacterial cell wall is impermeable to
many agents.
• Mycobacterial species are intracellular pathogens, and
organisms residing within macrophages are inaccessible to
drugs that penetrate these cells poorly.
 Mycobacteria (cont.)
• Mycobacteria are notorious for their ability to
develop resistance.
• Combinations of two or more drugs are required to
overcome these obstacles and to prevent emergence
of resistance during the course of therapy.
• The response of mycobacterial infections to
chemotherapy is slow, and treatment must be
administered for months to years, depending on
which drugs are used.
Definition
An antimycobacterial is a type of drug
used to treat mycobacteria infections.

Types include:

1. Tuberculosis treatments
2. Leprostatic agents
TB
•Is an infectious disease usually caused by the bacterium
Mycobacterium tuberculosis (MTB).
•It is spread through the air when people who have an
active MTB infection
cough, sneeze, or otherwise transmit their saliva through
the air.
Symptoms
chest pain, coughing up blood, and a productive,
prolonged cough for more than three weeks.
Systemic symptoms include fever, chills, night sweats,
appetite loss, weight loss, pallor, and fatigue.
 Drugs used in the treatment of
tuberculosis
Drugs used in the treatment of tuberculosis can be divided into two major
categories:
1. First-line drugs: Isoniazid, streptomycin, rifampicin, ethambutol, and
pyrazinamide.
2. Second-line drugs: Ethionamide, p-amino salicylic acid, ofloxacin,
ciprofloxacin, cycloserine, amikacin, kanamycin, viomycin, and
capreomycin.
First line
All first-line anti-tuberculous drug
names have a standard three-letter
and a single-letter abbreviation:
• Ethambutol is EMB or E,
• isoniazid is INH or H,
• pyrazinamide is PZA or Z,
• rifampicin is RMP or R,
• Streptomycin
Never use a single drug
Therapy
Isoniazid –rifampicin combination administered for 9
months will cure 95-98% of cases .

Addition of pyrazinamide for this combination for the

first 2 months allows total duration to be reduced to 6
months.
120

100

80
亚洲区
60 欧洲区
北美区
40

20

0
一月 二月 三月 四月
 Isonizid (INH)
•Isoniazid is the most active drug for the
treatment of tuberculosis caused by
susceptible strains.

•Isoniazid penetrates into macrophages

and is active against both extracellular
and intracellular organisms.

•In vitro, isoniazid inhibits most

tubercle bacilli in a concentration of
0.025~0.05 μg/mL or less and is
bactericidal for actively growing
tubercle bacilli. It is less effective
against atypical mycobacterial species.
Synthesis
 MOA
• Bacteriostatic at low conc. & bacteriocidal at high conc.
Especially against actively growing bacteria.

• Inhibits synthesis of mycolic acid is an essential components

of mycobacterial cell wall.

• Readily absorbed from GIT.

• Diffuse into all body fluids and Tissues Penetrates caseous

material and macrophages so it is effective against intra and
extracellular organisms.

• Metabolized in liver by acetylation.

• Excreted mainly in urine.

 SAR
1-Substitutionof hydrazine portion
of INH with alkyl and aralkyl
substitution resulted in a series of
active and inactive derivatives.

2-Substitution on the N2 position (R

1,R2=alkyl,R3=H)----active
compounds.

3 -Any Substitution atN1-

hydrogen(R3=alkyl)---------
destroy the activity.

4-Any Substitution---not superior

Ethambutol
 MOA
• Inhibits mycobacterial cell wall synthesis by
inhibiting arabinosyl transferase .
• Bacteriostatic
• Active against intra&extracellular bacilli .
• Well absorbed from gut.
• 20% excreted in feces and 50% in urine in
unchanged form.
• Crosses BBB in meningitis
 SAR

• Ethylene diamine chain --↑this chain length

--↓or destroy.
• Replacement of either N--↓or destroy.
• Increasing the size of Nitrogen
substituents--↓or destroy.
• Moving the location of alcohol groups--
↓ordestroy.
Pyrazinamide
 MOA

Pyrazinamide diffuses into the granuloma of M. tuberculosis, where the tuberculosis enzyme
pyrazinamidase converts pyrazinamide to the active form pyrazinoic acid.
 2nd line

• Indication of 2nd line treatment :

– Resistance to the drugs of 1st line.
– Failure of clinical response
– Increase of risky effects.
– Patient is not tolerating the
drugs first line drugs.
 Ethionamide
 Capreomycin
 Amikacin
 Ciprofloxacin & levofloxacin
 Rifapentine
 Aminosalicylic Acid (PAS)
 Ethionamide

MOA
– As isoniazid blocks synthesis of mycolic acid .
–Available only in oral form.
–Metabolized by the liver ,excreted by kidney.
– It is poorly tolerated because of :
• intense gastric irritation
• neurologic symptoms
• hepatotoxicity
 p-Aminosalicylic Acid
Once a very popular component in TB therapy, p-
aminosalicylic acid (PAS) is used as a second-line
agent today.

MO
A
PAS is thought to act as an antimetabolite interfering with the
incorporation of p-aminobenzoic acid into folic acid. When
coadministered with INH, PAS is found to reduce the acetylation
of INH, itself being the substrate for acetylation, thus increasing
the plasma levels of INH. This action can be especially valuable
in patients who are rapid acetylators.
 SAR
• Modification of the position of the hydroxy
and amino groups with respect to the carboxy
group resulted in a sharp decrease of activity.
• The amino group confers a distinct pharmacodynamic property to the
molecule, eliminating the antipyretic and analgesic activities of salicylic
acid and giving the specific tuberculostatic activity.

• nuclear substitution and replacement of the amino, hydroxy, or

carboxy groups with other groups yielded inactive or poorly active
products.

•Functional derivatives on the amino, hydroxy, and carboxy groups

of PAS are generally inactive, unless they are converted in vivo into
the active molecule.
 Leprosy
• Leprosy or Hansen's disease (HD) is a
chronic disease caused by the bacteria
Mycobacterium leprae and Mycobacterium
lepromatosis.

• granulomatous disease of the peripheral

nerves and mucosa of the upper respiratory
tract; skin lesions are the primary external
sign.
• Secondary infections, in turn, can
result in tissue loss causing fingers
and toes to become shortened and
deformed, as cartilage is absorbed
into the body
• usually spread from person to
person in respiratory droplets
 Drugs used in leprosy
• Dapsone
• Clofazimine
Dapsone (DDS, Diaminodiphenyl sulphone)
Dapsone, 4,4′-diaminodiphenylsulfone (34.2.3), is synthesized from either 4-
chloronitrobenzene or from the sodium salt of 4-acetamidobenzenesulfonic acid. Reacting
4-chloronitrobenzene with sodium sulfide gives 4,4′-dinitrodiphenylthioester (34.2.1), and
oxidation of the sulfur atom in this compound using potassium dichromate in sulfuric acid
gives 4,4′-dinitrodiphenylsulfone (34.2.2). Reduction of the nitro group in the resulting
compound using tin dichloride in hydrochloric acid makes the desired dapsone.
 MOA
• Inhibits folate synthesis.
–Well absorbed orally,widely
distributed .
– Half-life 1-2 days,tends to be retained
in skin,muscle,liver and kidney.
– Excreted into bile and reabsorbed in
the intestine.
– Excreted in urine as acetylated.
•As an antibacterial, Dapsone
inhibits bacterial synthesis of
dihydrofolic acid, via competition
with para-aminobenzoate for the
active site of dihydropteroate
synthase.

• Asan anti-inflammatory, Dapsone

inhibits the enzyme
myeloperoxidase. As part of the
respiratory burst that neutrophils
 SAR
Relpcemnet of 1 benzene ring results in
thiazosulfones— less active than DDS.

 Substitution on benzene ring results in

acetosulphone--↓activity, ↓g.i.t
irritation(bz increase solubility).

 Substitution by methanesulfinate
(CH2SO2)-gives
sulfoxone Na, which is water soluble, ↓g.i.t
irritation(bz increase solubility) –this drug
is preferred who can’t tolerate DDS-but
given 3times of DDS bz of its hydrolysis.
• Several derivatives of dapsone have been prepared in an
attempt to increase the activity. Isosteric replacement of one
benzene ring resulted in the formation of thiazolsulfone.
Although still active, it is less effective than dapsone.
Substitution on the aromatic ring, to produce acetosulfone,
reduced activity while increasing water solubility and
decreasing GI irritation. A successful substitution consists of
adding methanesulfi nate to dapsone to give sulfoxone
sodium.
• This water-soluble form of dapsone is hydrolyzed in vivo to
produce dapsone. Sulfoxone sodium is used in individuals
who are unable to tolerate dapsone because of GI irritation,
but it must be used in a dose threefold that of dapsone
because of ineffi cient metabolism to dapsone.
• The chemical modifi cation of dapsone derivatives continues
to be pursued with the intent of fi nding newer agents useful
Clofazimine
 MOA
• It is a phenazine dye.
• Unknown mechanism of action ,may be DNA
binding.
• Antiinflammatory effect.
• Absorption from the gut is variable.
• Given orally , once daily.
• Excreted mainly in feces.
• Stored mainly in reticuloendothelial tissues and skin.
• Half-life 2 months.
• Delayed onset of action (6 weeks).
Thank
you