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BY

MAHATHI
CONTENTS
► INTRODUCTION

► DRUG TARGET

► TARGETS FOR ANTI TUBERCULAR DRUGS

► DRUGS
INTRODUCTION
Tuberculosis is a chronic Infectious disease

caused by M.tuberculosis
mainly affecting the lung causing PTB
also affect other parts causing EPTB

Characterized by

► Cough lasting > 3 wks and not respond to usual


antibiotic
► Production of purulent, sometimes blood- stained
sputum
► Evening rise of temp.
► Night sweats
► Weight loss 
DRUG TARGET
► A drug target is a key molecule involved in a particular 
metabolic pathway that is specific to a disease condition
or pathology, or to the infectivity or survival of a microbial
 pathogen

ESSENTIAL CHARACTERISTICS OF
TARGET

► Peculiar to bacteria
► Should interfere with some structure or process that is
essential to bacteria growth, survival, or both
► Represent growth-essential genes
1. ENZYMES INVOLVED IN
CELL WALL SYNTHESIS

ENOYL ACYL D-ALANINE


CARRIER RACEMASE AND
PROTEIN D-ALANINE
REDUCTASE LIGASE
DRUG:ISONIAZID
, ETHIONAMIDE DRUG:CYCLOSERI
NE
ARABINOSYL
TRANSFERASE
DRUG:ETHAMBUTOL
MYCOBACTERIUM
CELL WALL

Porin

Lipoarabinomannan(LAM)

Mycolates

Arabinoglycan

Peptidoglycan

Lipid Bilayer
Enoyl acyl carrier protein
reductase (InhA)
► The key enzymes involved in the type II fatty
acid biosynthesis pathway of M. tuberculosis.,
precursors of mycolic acids
► MabA (β ketoacyl carrier protein reductase) &
InhA together with kasA /B (β ketoacyl
synthase) form type 2 FA elongation systems
► Inhibition of these enzymes inhibits mycolic
acid synthesis, component of cell wall
INH

Isonic
ot- NADH isonicotin
catalase-
peroxidase inic radical ic acyl-
enzyme acyl or NADH
katG anion anion complex

Enoyl acyl FATTY ACID


reductase SYNTHESIS

Cell Mycolic
lysis acid
ISONIAZID
► Structure
ARABINOSYL TRANSFERASE
► Involved in arabinosylation of
arabinogalactan,major polysaccharide
of cell wall

► Arabinosylation is the conversion of D-


glucose to D-arabinose and the
transfer of arabinose into
arabinogalactan.
D-GLUCOSE D-ARABINOSE

ARABINOSYL
ETB
TRASFERASE

Mycobacterial

Arabinogalactan

Bacteri
a
ETHAMBUTOL
► Structure
D-ALANINE RACEMASE &
D-ALANINE LIGASE
► Theseare used in synthesis of
dipeptide( d-alanyl-d-alanine)

► Dipeptideis involved in cross linking of


peptidoglycan strands in cell wall of
bacteria

► Inhibitorsof this enzymes are developed


as anti-T.B drugs
L-ALANINE
D-ALANINE RACEMASE

D-ALANINE

D-ALANINE LIGASE

DIPEPTIDE
CYCLOSERINE
2 ENZYMES INVOLVED IN
TRANSCRIPTION PROCESS

RNA POLYMERASE
β SUBUNIT
EX: RIFAMPICIN
RNA polymerase
► Basic unit of bacterial transcription apparatus

► Holoenzyme consisting of core enzyme (2α,β,β’) and


protein (sigma factor)

► The sigma factors recognizes promoter region

► Some anti-bacterial drugs (most importantly,rifampicin)


kill bacteria by targeting this enzyme.
RIFAMPYCIN
► Structure
Rifampyc
in

translati
on
prokaryotic
DNA- transcripti Cell
on death
dependent
RNA polymerase

PROTEIN
RNA
3. TARGET IN
TRANSLATION PROCESS

RIBOSOMAL S12 PROTEIN


AND
16s rRNA
EX:STREPTOMYCIN
Ribosomal S12 protein and 16S
rRNA
► Involved in translation process
► It is a critical component of the 30S ribosomal
subunit and is involved in tRNA selection
► The 16s rRNA is part of the 30-S subunit
► Many antibiotics inhibit the growth of bacteria
by targeting protein biosynthesis
STREPTOMYCIN
► Structure
FORMYL METHIONYL t-RNA

30S (RIBOSOMAL S12


STREPTOMYCIN
SUBUNIT PROTEIN & 16S
rRna)

INITIATION OF PROTEIN
SYNTHESIS

DEATH OF
MICROBIAL CELL
4. ENZYME INVOLVED IN
DNA REPLICATION

DNA GYRASE
EX: FLUOROQUINOLONES
DNA GYRASE OR
TOPOISOMERASE II
► DNA gyrase is an ATP-dependent enzyme that
acts by creating a transient double-stranded
DNA break
► It is unique in catalyzing the negative
supercoiling of DNA and is essential for
efficient DNA replication, transcription, and
recombination
► DNA gyrase is thus a validated target for anti-
tubercular drug
FLUOROQUINOLONES
► Examples include ciprofloxacin,
ofloxacin,moxifloxacin and
sparfloxacin

CIPROFLOXACI
N
OFLOXACIN
5.ENERGY PRODUCTION
PATHWAY
► Energy production or maintenance is
important for the viability of persistent
nongrowing tubercle bacilli
► Energy production pathways, such as
the electron transport chain,glycolytic
pathways (like the Embden–Meyerhof
pathway) and fattyacid production
pathways, could be good targets for TB
drug development
PYRAZINAMIDE
► STRUCTURE
MOA OF PYRAZINAMIDE

PYRAZINAMIDASE

PYRAZINOIC
PYRAZINAMIDE ACID

FATTYACID FATTY ACID


SYNTHETASE Ι SYNTHESIS
FLOURO
QUINO
LONES
THANK
YOU 