New agents for the treatment of drug resistant Mycobacterium Tuberculosis

NEW AGENTS FOR THE TREATMENT OF
DRUG-RESISTANT
MYCOBACTERIUM TUBERCULOSIS
Source of article :
http://www.sciencedirect.com/science/article/pii/S0169
409X16301363
1

INTRODUCTION
 In 1946 the world begin treatment with streptomycin , then the
four drug therapy appear , INH , RIF , EMB , PZA , and due to the
resistance , of MT to INH , RIF that expressed in 3.5% of the
naive infection , in addition of the appearance of MDR-TB .
Wich cause 20.5% of people with MDR-TB relapse again .
 However a complicated complication appear with RIF treatment
patient who diagnosied with HIV as it is an inducers for antiviral
drug metabolism by cytochrom p450,so HIV drugs can not be
given with the RIF that lead to very poor prognosis. Especially
patient with MDR-TB .
 The appearance of MDR-TB , lead to second line agents
appearing , then last decades the XDR-TB appear wich is it a
resistance of all first line therapy drugs and fluroquinilones ,
reaching to the appearance of TDR-TB in China , Africa ,
Eastern Europe , wich it a resistance to all available drugs , that
increase the need of new therapies .!! 3

THIS REGIMEN IMPLEMENTS THE FOLLOWING FIVE MAIN ELEMENTS
TO INCREASE SURVIVAL AND DECREASE TRANSMITTANCE FOR MOST
DEVELOPING COUNTRIES BY WHO :
 government commitment to monitoring and treating Mtb infections.
 sputum-smear microscopy for all cases to assess drug susceptibility.
 standardized treatment regimens with direct observation by a trained
healthcare professional.
 Uninterrupted drug supply.
 standardized reporting system to maximize data interpretation directly from
patients' medical records.
This approach has reduced the overall number of TB infections and
deaths, but it has not affected the increasing numbers of MDR-TB
infections . Therefore, more chemotherapeutic interventions are
needed
5

TUBERCULOSIS LIFE CYCLE AND
MICROENVIRONMENT :
7

IMIDAZOPYRIDINE (Q203)
Company : Janssen
MOA:
 act on respiratory chain ,that target cytochrome b subunite
(QcrB), of the cytochrome bc1 , it is essential component in
respiratory electron chain of ATP synthesis , cause rapid
depletion in ATP .
 Killing profile :
 they have excellent killing profile for chronic MTB,(it use in
latent TB so this drug can penetrate the macrophages and
granuloma to kill TB that display dose depent growth inhibitor
, use for MDR tb , Q203 causes a rapid depletion of
intracellular ATP at an IC50 of 1.1 nM and interrupts ATP
homeostasis in dormant Mtb at an IC50 of 10 nM.
 Q203, has an MIC50 of 2.7 nM in broth media and 0.28 nM
inside the macrophage.
9

 Administration :
 Phase I trials begun with orally 100mg dose once daily that
will be adjusted according to pharmacokinetics analysis .
 Distribution:
 The volume of distribution was moderate (5.27 L per kg body
weight).
 Execretion:
 and the systemic clearance was low (4.03 ml min−1 kg−1).
The drug concentration in lungs was two- to threefold higher
than in the serum.
 Combination:
 Combination the drug with second line agents to treat MDR-
TB .
 Side effect:
 No side effects . 13

PHARMACOKINETIC OF THE DRUG :
reported PK and safety profile:
 It given once daily oral dosing, with 90% oral bioavailability in
mice, and a half-life of almost 24 h.
Cytotoxicity :
 There was no detection , of cytotoxicity in vitro or in vivo, no
signs of hERG inhibition , but it (indicative of limited
cardiotoxicity), and mice tolerated 1 g/kg doses for 2 weeks.
Drug –Drug interaction :
 Q203 did not inhibit any P450 isoforms and was not a
substrate or inhibitor of P-gP efflux,which indicated a low risk
of drug–drug interactions. Though it should be noted that like
Bedaquiline, Q203 is a highly lipophilic drug,with very high
serum protein binding.
14

FEROPENEM
 Brand name: Orapem
 Generic name: faropenem medoxomil
 Company: Replidyne, Inc.
 Drug Class :B-Lactam antibiotics
15

TREATMENT
 Acute bacterial sinusitis
 Community-acquired pneumonia
 Acute exacerbations of chronic bronchitis
 Uncomplicated skin and skin structure infections
 Urinary tract infections
16

MECHANISM OF ACTION
 Feropenem 200 mg tablet is an antibiotic. It kills the
bacteria by attacking their cell wall. Specifically, it
prevents the synthesis of a substance in the cell
wall called peptidoglycan, which provides the cell
wall with the strength required for survival of
bacteria in human body
17

SIDE EFFECTS
Angioedema (swelling of deeper layers of skin)
Decreased blood pressure,
Diarrhoea, Dizziness, Shortness of breath,
Flushing, Increased sweating,
Feeling of discomfort, Black and bloody stools,
Renal impairment, Ringing in ear, Stomach pain,
Wheezing
18

DPRE1 INHIBITORS :
PBTZ 169
BTZ 043
TCA11,4-azaindols
Delamanid
19

DECAPRENYLPHOSPHORYL-Β-D-RIBOSE 2′-
EPIMERASE 1 (DPRE1)
DprE1, in combination with DprE2, catalyzes the
epimerization of decaprenylphosphoryl-β-Dribose to
the corresponding of decaprenylphosphoryl-β-D-
arabinose, thereby providing a crucial precursor to
the cell wall arabinogalactan polysaccharide via a
series of sequential oxidation–reduction reactions .
This target is frequently identified as the
mechanism of action of hits identified in whole-cell
phenotypic.
20

TCA1
 TCA1 was discovered that has activity against
replicating and nonreplicating Mycobacterium
tuberculosis. It is also efficacious in acute and
chronic rodent models of TB alone or combined
with frontline TB drugs.
 brand name : Calbiochem®
 Manufacturer: EMD Millipore
21

 MOA : TCA1 functions by a unique mechanism
 prevent the formation of biofilm Because TCA1
had diminished activity against the
DprE1,which required for Mycobacterium cell wall
arabinan biosynthesis
 2 it band to MoeW, a protein involved in the
biosynthesis of the molybdenum cofactor (MoCo)
MoCo is essential for the nitrate respiratory and
assimilatory function of Mtb nitro-reductase. Some
of these nitro-reductases have been found to be
involved in the response of Mtb to hypoxia and
nitric oxide 23

 Antimicrobial spectrum : work against
mycobacterium that has very narrow spectrum ,
and can act against ,XDR – TB , MDR- TB , wild
type –TB .
24

 Administration :
 oral administration of 20 and 50 mg/kg in solution
formulation

 metabolism and drug – drug interaction :
 TCA1 has no inhibitory activity against four CYP
enzymes.
 Bioavailability: ranging from 19% to 46%,
 Excretion :
 TCA1 exhibited a low clearance and steady-state
volume of distribution, with an elimination half-life of
0.73 h. After IV adminstration , and a half-life of 1.8 h
after oral admnstraton ,
25

 Areej Abu Hanieh
 Sondos Hassouneh
 Shereen Rawajbeh
 Instructor : Abdullah Rabba
26

New agents for the treatment of drug resistant Mycobacterium Tuberculosis

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