ANTI-TUBERCULOSIS DRUGS
ANTI-TUBERCULOSIS DRUGSTuberculosis (TB) is a disease that has
affected mankind for centuries and dates as far back as ancient
Egyptian times.is caused by a slow growing bacterium called M.
tuberculosis.The disease is spread by coughing, talking, spitting
or sneezing which spreads the mycobacteria through the air in tiny
droplets of water which are inhaled in to the lungs.
ANTI-TUBERCULOSIS DRUGSThe primary location of the disease is in
the lungs, called pulmonary TB, where bacterial growth destroys
tissue making it very hard for the patient to breathe resulting in
death.symptoms can also include meningitis, legions on the skin and
degradation of the heart, bones and intestines.The difficulty in
managing tuberculosis is the prolonged treatment duration, the
emergence of drug resistance and co-infection with HIV/AIDS.
ANTI-TUBERCULOSIS DRUGSTuberculosis control requires new drugs
that act at novel drug targets to help combat resistant forms of
Mycobacterium tuberculosis and reduce treatment duration.Drug
resistant strains of the mycobacterium are not susceptible to the
current cocktail of drugs available. now infects approximately one
third of the worlds population and causes 8 million new cases of TB
each year resulting in around 2 million deaths worldwide. The
resurgence has been caused due to three main reasons:The available
chemotherapy is not very efficacious and has to be given as a
precise combination over a period of months (poor compliance). Drug
resistant strains of the mycobacterium are not susceptible to the
available drugs.There is also a strong epidemiological coexistence
between TB with HIVMycobacterium tuberculosisis the principal
causative agent of TB in human.is a slow growing Gram-positive
rod-shaped bacterium that has a thick, rigid, and hydrophobic cell
wall which serves to protect the organism from the environment,
making it highly impermeable to conventional antimicrobial
agents.
The current treatment of TBTB is treated in two phases. There is
an initial phase and a continuation phase and depending upon the
patients ability to comply with the drug regime:Phase-I: Here there
is the concurrent use of at least three drugs to reduce the
bacterial population as rapidly as possible in order to prevent
resistance.as a combination preparation or triple therapy.isoniazid
(INH), rifampicin (RIF) and pyrazinamide (PZA).Streptomycin (SM)
may be used in cases where resistance to INH has been
established.The initial phase drugs are normally used for two
monthsThe current treatment of TBPhase-II: After the initial phase,
a further four months of chemotherapy is carried out using
preferably a combination of RIF and INH.
Potential targets in M. tuberculosis Targeted pathways should be
unique to the Mycobacterium.Many agents have been introduced to
target certain metabolic sites:Inhibit cell wall
biosynthesis.Affect protein biosynthesis.Affect DNA replication and
transcription.Inhibit fatty acid synthesis (FAS).
Mycobacterial cell walla very complicated cell wall which is
sometimes described as waxy because of its complex fatty acid
barrier which makes getting a drug molecule into the cytoplasm
extremely difficult.Consists mainly from special type of fatty
acids called mycolic acids which make mycobacterium exceptionally
different from other gram +ve bacteria regarding the cell wall
permeability.
Mycobacterial cell wall
Mycolic acidsMycolic acidsare -hydroxy C54-63 fatty acids with a
long -alkyl side chain of C22-24 in length.play important roles in
the mycobacterium, including resistance to chemical injury;
resistance to dehydration, low permeability to polar molecules and
allow the bacterium to grow readily inside macrophages-mycolic
acids are the predominant form (70%)
Synthesis of -mycolic acid Targeting mycolic acid
biosynthesis
Isoniazid (INH) 1952 a purely synthetic agent.Has bacteriostatic
action at lower dose and bactericidal at higher
concentration.Inhibits fatty acid biosynthesis by interfering with
InhA enzyme (essential one).It is a prodrug and has to be activated
before killing the bacteria.
Activation of INH
isonicotinic acyl-NADH complex will tightly bound to the active
site of InhA thus preventing access of the natural enoyl-AcpM
substrateINH pharmacokinetic profileINH is well absorbed orally or
intramuscularly and distributes well throughout the body (Why?).
(LogP= -0.64).its metabolism occurs initially by liver
N-acetyltransferase. This means that patients who are poor
acetylators can experience toxicity problems as acetylation of INH
is first required before the hydrolysis can occur and the drug
cleared by the kidneys
INH resistanceTwo major resistant mechanism have been
reported:Resistance to INH generally occurs when the drug is
administered alone for 3 months and is caused mainly due to the
absence of the gene encoding the catalase-peroxidase katG which
prevents activation of the drug.Mutations in InhA have also been
identified and considered as a reason for resistance to the
drug.
Pyrazinamide (PZA) 1952drug is a synthetic analogue of
nicotinamide.is bactericidal against growing bacteria.The exact
mechanism of action of this unclear, but there are two proposed
ones:Affect memebrane transport.Inhibit FAS-I system: This
interferes with the bacteriums ability to synthesize new fatty
acids, required for growth and replication.it is known that PZA is
a prodrug which requires activation to pyrazinoic acid (POA) by the
Pyrazinamidase enzyme:
Pyrazinamide pharmacokinetic profilePZA is well absorbed orally
and distributes well throughout the body (Why?) reaching
concentration levels above that needed to kill the tubercle
bacilli.LogP = -0.42It is metabolized by the liver to give mainly
Pyrazinoic acid which is then excreted by the kidneys.It is also
known that resistance to PZA rapidly evolves if the drug is used
alone and is associated with mutation in the pncA gene which
encodes the Pyrazinamidase/ nicotinamidase enzyme.PyrazinamideMore
selective on M.tuberculosis than other mycobacterium species as
well as other bacterial strains such as E. coli (Ying Zhang,
2008).
This is thought to be due to effective efflux pump in those
bacterial cells compared to M.tuberculosis which will pump PZA as
pyrazinoic acid out of the cell. D-Cycloserine (CS) 1952 possesses
a broad range of anti-mycobacterial activity.It works by mimicking
D-alanine which is the natural substrate for the enzyme D-alanine
racemase (Alr) and D-alanine: D-alanine ligase (Ddl) thus
preventing the synthesis of the mycolyl peptidoglycan which lead to
cell death.
D-Cycloserine pharmacokinetic and resistant profileCS is readily
absorbed orally and widely distributed amongst tissues before being
excreted by the kidneys with little of the drug being
metabolized.
Alr serves to convert L- aniline (bacteria utilize L- aniline
from the host environment) to D-alanine and mutation in the active
site of this enzyme have been proposed to be responsible for the
resistance of CS.
Not active against MDR-TB.
Future TB drugsRecent research regarding anti-tuberculosis
agents is interested in:shortening treatment time.combating
MDR-TB.and finding effective agents against persisting bacterial
infections.Most of the work in this field focused in finding agents
selective on inhibiting FAS-II system (specifically targeting new
and essential enzymes), especially preventing mycolic acid
biosynthesis.
Possible new targets for anti-TB agents1234Case study for the
development of new anti-TB agents.
TLM; a natural product form Nocardia, inhibits KasA and KasB
(FAS-II).
Inactive on the whole bacteria (why?).
difficult to separate and synthesize.Molecular Modelling and
Computer-Aided Drug DesignIs the use of the three dimensional
structure of macromolecular targets to design novel inhibitors.
Then using computational docking programs to dock hypothetical
structures into the binding site.
the compounds then will be rank-ordered with respect to their
goodness of fit.
Compounds will be synthesized and tested on both the isolated
enzyme and the whole bacterial cell.
Heath et al. 2001TLM-Enzyme
2-aminobenzimidazole-ecFabB
4-aminoimidazole-ecFabB
Findings form modeling results TLM bound in the same pattern as
reported in literature.
Increasing the hydrophobic character of the compound improved
the binding.
The carbonyl group is essential for H-bonding.
The in-vitro results showed promising activity in submicromolar
range against M.tuberculosis.