Department of Chemical Drugs, Faculty of Pharmacy, Masaryk university, Brno1
Design of new antituberculotics
Mgr. Veronika Ballayová
Design of new antituberculotics2
Parts of the presentation
1. Tuberculosis (basic facts, statistics & current situation, mortality, resistance)
2. Treatment
2.1. First-line drugs
2.2. Second-line drugs
3. New drug candidates
3.1. Pre-clinical development
3.2. Clinical development
3.3. Optimizing the use of approved and repurposed drugs
Design of new antituberculotics3
Tuberculosis (TB)
̶ Multisystemic infectious and communicable disease
̶ One of the leading causes of death worldwide
̶ Until the COVID-19 pandemic, TB was the leading cause of death
from a single infectious agent, ranking above HIV/AIDS
̶ WHO has published a global TB report every year since 1997 (to
provide a comprehensive and up-to-date assessment of the status
of the TB epidemic)1
1 https://www.who.int/publications/i/item/9789240037021
Design of new antituberculotics4
Tuberculosis (TB) – basic facts
̶ Old disease (affected humans for thousands of years)
̶ Active / latent form
̶ Caused by the bacillus Mycobacterium tuberculosis (M. avium, M. fortuitum, M. kansasii)
̶ Germs are spread from person to person through the air by expel infectious droplets (caught,
squeeze or split)
̶ Infects mainly the lungs (pulmonary TB), also affects other organs and tissues
(extrapulmonary TB)
̶ Most of the infected people live in low- and middle-income countries, BUT TB is present all
over the world
̶ About half of all people with TB can be found in 8 countries: Bangladesh, China, India,
Indonesia, Nigeria, Pakistan, Philippines and South Africa1
1 https://www.who.int/publications/i/item/9789240037021
Design of new antituberculotics5
Mycobacterium tuberculosis
̶ Slowly growing, aerobic bacteria
̶ They can grow within body cells (an intracellular parasitic
bacterium).
̶ Divides every 16 to 20 hours (extremely slow rate compared
with other bacteria, which usually divide in less than an hour).
̶ Unique outer membrane lipid bilayer cell wall with mycolic
acid, which helps them to protect against host immune system
̶ It may take 9 weeks for these slow-growing bacteria to grow
on specialised media.
Design of new antituberculotics6
Tuberculosis (TB) – statistics
̶ About a quarter of the world´s population is infected with M. tuberculosis (2 billion people)
BUT only 5-15% of these people will fall ill with active form of the disease (the rest have TB
infection but are not ill and cannot transmit the disease)1
̶ Mostly affects adults (90%), but all age groups are vulnerable, more cases among men than
women2
̶ People with weak immune system - higher risk of infection (HIV infection – 18 times more
likely to develop active tuberculosis)2
̶ Other risk factors: undernutrition, diabetes, smoking and alcohol consumption
1 https://www.who.int/publications/i/item/9789240037021
2 https://www.who.int/news-room/fact-sheets/detail/tuberculosis
Design of new antituberculotics7
Global TB report
̶ Concept of a „high burden country“ (HBC)
̶ 3 global HBC lists for 2021-2025:1
̶ TB
̶ HIV-associated TB
̶ MDR-TB and RR-TB
̶ TB data profiles are available online for all 215 countries
̶ Free WHO TB Report mobile app
1 https://www.who.int/publications/i/item/9789240037021
Design of new antituberculotics8
Countries in the 3 global lists of high-burden countries in the period of
2021-2025 by WHO1
1 https://www.who.int/publications/i/item/9789240037021
Design of new antituberculotics9
Tuberculosis- current situation
̶ Large global drop in the number of people newly diagnosed with TB and reported in 2020,
compared with 2019
̶ 2019 – 2020 18% decrease
̶ Reduction in the regions of:
̶ South-East Asia
̶ Western Pacific
̶ African Region (2,5%)
̶ European Region
These 2 regions accounted for most
(84%) of the global reduction (namely
India 41%, Indonesia 14%, Philippines
12%, China 8%)
https://www.who.int/publications/i/item/9789240037021
10
Tuberculosis - mortality
̶ TB – 13th leading cause of death worldwide
̶ Increasing number of deaths in 2020
̶ Number of deaths officially classified as caused by TB -1.5 million
̶ including 214 000 people with HIV1
̶ TB remains one of the world´s top infectious killers
1 https://www.who.int/publications/i/item/9789240037021
Design of new antituberculotics11
Tuberculosis (TB) - treatment
̶ Curable and preventable
̶ Without treatment – mortality rate from TB is high
̶ Effective drug treatments were first developed in the 1940s
̶ Currently recommended treatment: 6-month regiment of four first-line drugs: isoniazid,
rifampicin, ethambutol and pyrazinamide
̶ 85% of patients with TB disease can be successfully treated with a 6-month drug regiment –
universal health coverage1
̶ Vaccine for prevention of TB – BCG vaccine (bacille Calmette-Guérin) – prevents severe
forms of TB in children
1 https://www.who.int/news-room/fact-sheets/detail/tuberculosis
Design of new antituberculotics12
Tuberculosis (TB) – resistance
̶ Rifampicin-resistant TB (RR-TB)
̶ Multidrug-resistant TB (MDR-TB) defined as resistance to isoniazid and rifampicine
(the most powerful anti-TB drugs)
̶ treatment is longer (up to 2 years), more toxic and more expensive – second-line drugs
̶ HIV/AIDS antiretroviral therapies are not compatible with the current TB regiment because
of shared drug toxicities and drug interactions (rifampicin-induced cytochrome P450
activation)
̶ Urgent need for research and development of new drug structures with activity against
resistant bacteria
13
Treatment:
first-line drugs
̶ More than 40 years old
̶ Non-compliance of the patients
CHETTY, Sarentha, Muthusamy RAMESH, Ashona SINGH-PILLAY a Mahmoud E. S. SOLIMAN. Recent
advancements in the development of anti-tuberculosis drugs. Bioorganic & Medicinal Chemistry Letters
[online]. 2017, 27(3), 370–386. ISSN 0960-894X. Dostupné z: doi:10.1016/j.bmcl.2016.11.084
14
Treatment:
second-line drugs
̶ Treatment is:
̶ longer (up to 2 years)
̶ more toxic
̶ more expensive
CHETTY, Sarentha, Muthusamy RAMESH, Ashona SINGH-PILLAY a Mahmoud E. S.
SOLIMAN. Recent advancements in the development of anti-tuberculosis drugs.
Bioorganic & Medicinal Chemistry Letters [online]. 2017, 27(3), 370–386. ISSN 0960-
894X. Dostupné z: doi:10.1016/j.bmcl.2016.11.084
Design of new antituberculotics15
New drug candidates
̶ Since the 1990´s, there has been a resurgence of interest in new anti-TB drugs development,
as TB once became an internationally significant public health risk.
̶ Rapid appearance of resistance to the available drugs, bacterial persistence, latency,
long-treatment durations – results in poor adherence and urgency of new drug development
̶ Ideal properties of the new regiment:1
̶ A shorter treatment duration
̶ A good bactericidal and sterilising activity against all TB bacterial sub-population
̶ A better safety and tolerability profile than existing anti-TB drugs
̶ Compatibility with other drugs used in TB chemotherapy and for those patients co-infected
with HIV
1 CHETTY, Sarentha, Muthusamy RAMESH, Ashona SINGH-PILLAY a Mahmoud E. S. SOLIMAN. Recent advancements in the development of anti-tuberculosis
drugs. Bioorganic & Medicinal Chemistry Letters [online]. 2017, 27(3), 370–386. ISSN 0960-894X. Dostupné z: doi:10.1016/j.bmcl.2016.11.084
Define footer – presentation title / department16
New drug candidates
̶ Currently, there are a number of drug candidates in different phases of the discovery, preclinical
and clinical development
̶ There are also a number of ongoing trials using repurposed drugs in different combinations
and doses of drugs that are currently on the market
CHETTY, Sarentha, Muthusamy RAMESH, Ashona SINGH-PILLAY a Mahmoud E. S. SOLIMAN. Recent advancements in the development of anti-tuberculosis
drugs. Bioorganic & Medicinal Chemistry Letters [online]. 2017, 27(3), 370–386. ISSN 0960-894X. Dostupné z: doi:10.1016/j.bmcl.2016.11.084
Define footer – presentation title / department17
CHETTY, Sarentha, Muthusamy RAMESH, Ashona SINGH-PILLAY a Mahmoud E. S. SOLIMAN. Recent advancements in the development of anti-tuberculosis
drugs. Bioorganic & Medicinal Chemistry Letters [online]. 2017, 27(3), 370–386. ISSN 0960-894X. Dostupné z: doi:10.1016/j.bmcl.2016.11.084
Design of new antituberculotics18
Pre-clinical development
̶ CPZEN-45
̶ Nucleoside antibiotic, which works through the inhibition of decaprenyl-phosphateGlcNAc-1-phosphate
transferase
̶ In vitro activity against both replicating and non-replicating bacteria
̶ Efficacy against both drug-sensitive and MDR-TB in murine models
̶ SQ-609
̶ Dipiperidine pharmacophore
̶ TBI-166
̶ Riminophenazine class of drugs
̶ Clofazimine (antileprotic drug) – several undesirable properties
(urine discoloration, poor solubility,...)
̶ Obtained through lead optimization to keep the efficacy
without undesirable properties
CHETTY, Sarentha, Muthusamy RAMESH, Ashona SINGH-PILLAY a Mahmoud E. S. SOLIMAN. Recent advancements in the development of anti-tuberculosis
drugs. Bioorganic & Medicinal Chemistry Letters [online]. 2017, 27(3), 370–386. ISSN 0960-894X. Dostupné z: doi:10.1016/j.bmcl.2016.11.084
Design of new antituberculotics19
Clinical development
̶ Q203
̶ Optimised from an imidazole[1,2-α]pyridine amide
̶ Works in anaerobic and aerobic conditions
̶ Inhibition against both intra-cellular and extra-cellular TB as well as replicating and nonreplicating
bacteria
̶ Target: respiratory cytochrome bc1 complex – inhibition of the synthesis of ATP
̶ Sutezolid (PNU-100480)
̶ Analogue of linezolid
̶ Superior antimycobacterial activity and
safety profile compared with linezolid
CHETTY, Sarentha, Muthusamy RAMESH, Ashona SINGH-PILLAY a Mahmoud E. S. SOLIMAN. Recent advancements in the development of anti-tuberculosis
drugs. Bioorganic & Medicinal Chemistry Letters [online]. 2017, 27(3), 370–386. ISSN 0960-894X. Dostupné z: doi:10.1016/j.bmcl.2016.11.084
Design of new antituberculotics20
Clinical development
̶ SQ109
̶ Diamine analogue of ethambutol
̶ Unsaturated isoprenyl units and a bulky adamantyl ring
̶ Limited bioavailability
̶ Large volume of distribution into various tissues, particularly the lungs
̶ Rapidly metabolised in the liver
̶ Mechanism of action: inhibition of the cell wall synthesis
̶ Oral administration with a long half-life (once-a-week dosing)
̶ Combined administration with rifampicin exhibit synergistic in vitro activity without
antagonistic interactions
̶ Combination with isoniazid exhibit synergistic in vivo
RIVERS, Emma C. a Ricardo L. MANCERA. New anti-tuberculosis drugs in clinical trials with novel mechanisms of action. Drug Discovery Today [online].
2008, 13(23), 1090–1098. ISSN 1359-6446. Dostupné z: doi:10.1016/j.drudis.2008.09.004
Design of new antituberculotics21
Clinical development
̶ Pretomanid (PA-824)
̶ Bicyclic nitroimidazofurans – active against M. tuberculosis – MUTAGENIC
̶ Bicyclic nitroimidazo[2,1-b]oxazine – equal activity without mutagenic features
̶ Prodrug (metabolised by M. tuberculosis)- probably bioreduction of its aromatic nitro group
to a reactive nitro radical anion intermediate
RIVERS, Emma C. a Ricardo L. MANCERA. New anti-tuberculosis drugs in clinical trials with novel mechanisms of action. Drug Discovery Today [online].
2008, 13(23), 1090–1098. ISSN 1359-6446. Dostupné z: doi:10.1016/j.drudis.2008.09.004
Design of new antituberculotics22
Clinical development
̶ Pretomanid (PA-824)
̶ NO cross-resistance to other current anti-TB drugs
̶ Treatment of latent TB (activity against persistent bacilli)
̶ Long half-life, accumulate in the body
̶ Mechanism of action: two-fold
1. Inhibition of M. tuberculosis cell wall lipid and protein synthesis
2. Activity against non-replicating bacteria – probably due to the production of nitric oxide which
is most likely generated on conversion of the prodrug to its active form
̶ Combination with moxifloxacine – particularly effective with no relaps
CHETTY, Sarentha, Muthusamy RAMESH, Ashona SINGH-PILLAY a Mahmoud E. S. SOLIMAN. Recent advancements in the development of anti-tuberculosis
drugs. Bioorganic & Medicinal Chemistry Letters [online]. 2017, 27(3), 370–386. ISSN 0960-894X. Dostupné z: doi:10.1016/j.bmcl.2016.11.084
Design of new antituberculotics23
Clinical development
̶ Delamanid (OPC-67683)
̶ 6-nitro-2,3-dihydroimidazo[2,1-b]oxazole
̶ Prodrug – M. tuberculosis metabolises the drug and produces one main metabolite:
desnitro-imidazooxazole
RIVERS, Emma C. a Ricardo L. MANCERA. New anti-tuberculosis drugs in clinical trials with novel mechanisms of action.
Drug Discovery Today [online]. 2008, 13(23), 1090–1098. ISSN 1359-6446. Dostupné z: doi:10.1016/j.drudis.2008.09.004
Design of new antituberculotics24
Clinical development
̶ Delamanid (OPC-67683)
̶ Excellent in vitro activity against drug-susceptible and resistant M. tuberculosis strains
̶ NO cross-resistance to any current first-line drugs
̶ Infrequent and low dosing
̶ Long half-life, lack of metabolization by CYP enzymes
̶ Efficacy in immunocompromised mice – potential treatment of co-infected TB/HIV patients
̶ Mechanism of action: inhibition of methoxy-mycolic and keto-mycolic acid synthesis
̶ Combination with the first-line drugs – NO antagonistic interactions
̶ Combination of delamanid, linezolid, levofloxacin and pyrazinamide
CHETTY, Sarentha, Muthusamy RAMESH, Ashona SINGH-PILLAY a Mahmoud E. S. SOLIMAN. Recent advancements in the development of anti-tuberculosis
drugs. Bioorganic & Medicinal Chemistry Letters [online]. 2017, 27(3), 370–386. ISSN 0960-894X. Dostupné z: doi:10.1016/j.bmcl.2016.11.084
RIVERS, Emma C. a Ricardo L. MANCERA. New anti-tuberculosis drugs in clinical trials with novel mechanisms of action. Drug Discovery Today [online]. 2008,
13(23), 1090–1098. ISSN 1359-6446. Dostupné z: doi:10.1016/j.drudis.2008.09.004
Design of new antituberculotics25
Clinical development
̶ Bedaquiline (TMC-207)
̶ Diarylquinoline
̶ Mechanism of action: inhibition of Mycobacterium membrane-subunit c of ATP synthase
̶ Excellent activity against drug-susceptible, MDR-TB and RR-TB
̶ NO cross-resistance to current first-line drugs
̶ Use of TMC207 alone appears to be at least as effective as a combination of rifampicin,
isoniazid and pyrazinamide
̶ Orally well-absorbed with a long half-life (single weekly dosing)
̶ Metabolised by CYP3A4 – incompatible with anti-retrovirals
̶ Synergistic effect for the combination TMC207 and pyrazinamide – 2 months to completely
eradicate lung M. tuberculosis (pyrazinamide indirectly inhibites aTP synthesis)
̶ Bedaquiline – Pretonamid – Pyrazinamide combination is currently in phase III clinical
trials for the treatment of MDR-TB
CHETTY, Sarentha, Muthusamy RAMESH, Ashona SINGH-PILLAY a Mahmoud E. S. SOLIMAN. Recent advancements in the development of anti-tuberculosis
drugs. Bioorganic & Medicinal Chemistry Letters [online]. 2017, 27(3), 370–386. ISSN 0960-894X. Dostupné z: doi:10.1016/j.bmcl.2016.11.084
RIVERS, Emma C. a Ricardo L. MANCERA. New anti-tuberculosis drugs in clinical trials with novel mechanisms of action. Drug Discovery Today [online]. 2008,
13(23), 1090–1098. ISSN 1359-6446. Dostupné z: doi:10.1016/j.drudis.2008.09.004
Design of new antituberculotics26
CHETTY, Sarentha, Muthusamy RAMESH, Ashona SINGH-PILLAY a
Mahmoud E. S. SOLIMAN. Recent advancements in the
development of anti-tuberculosis drugs. Bioorganic & Medicinal
Chemistry Letters [online]. 2017, 27(3), 370–386. ISSN 0960-894X.
Dostupné z: doi:10.1016/j.bmcl.2016.11.084
Design of new antituberculotics27
Optimizing the use of approved and
repurposed drugs
̶ Rifampicin
̶ Higher doses of 15 or 20 mg/kg
̶ Increase in dose had no corresponding increase
in adverse effects
̶ Rifapentine
̶ Reducing the treatment durations of drug-susceptible TB
and the treatment of latent TB
̶ Once-weekly dosing
̶ Moxifloxacin
CHETTY, Sarentha, Muthusamy RAMESH, Ashona SINGH-PILLAY a Mahmoud E. S. SOLIMAN. Recent advancements in the development of anti-tuberculosis
drugs. Bioorganic & Medicinal Chemistry Letters [online]. 2017, 27(3), 370–386. ISSN 0960-894X. Dostupné z: doi:10.1016/j.bmcl.2016.11.084
Design of new antituberculotics28
Summary
̶ A number of new anti-TB drugs have been developed in recent years with novel mechanism
of action, exhibit excellent activity against M. tuberculosis and reduce the duration of
treatment and dosing.
̶ The structure OPC-67683 (Delamanid) may be effective in HIV/AIDS patients and
TMC207(Bedaquiline) may be effective against MDR-TB.
̶ There are a number of other drug molecules in clinical or pre-clinical trials, although there is
limited information available.
̶ These developments give hope that within the next decade more effective anti-TB drugs may
be achieved.
Design of new antituberculotics29
Thank you for your attention.