Tuberculosis Drug Discovery

Priscille Brodin,
INSERM France,
Research Director
 TB is cured with Antibiotherapy

Lung Disease caused by Mycobacterium tuberculosis

Tubercle Bacillus

Complex bacterial cell envelope

All current TB drugs are antibiotics

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 Current drug treatment for TB

Antibiotherapy: 6 months

Drug sensitive TB:

4 first-line antibiotics: Isoniazid, (INH) Rifampin (RIF), Ethambutol
(EMB), Pyrazinamide (PZA)

Drug resistant MDR/XDR:

Second-line antibiotics: Aminoglycosides (KM, Amk, Cm, Stm),
Fluoroquinolones, Ethionamide (ETH),
Novel drugs: Bedaquiline, Delamanid

https://www.tbfacts.org/tb-drugs/

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 Why searching for new TB Drugs?

Need for specific therapeutic indications:

Multi-Drug Resistant, Extremely Drug resistant, MDR-XDR TB
Immunocompromised Host
HIV-positive, Rheumatoid Arthritis, Diabetes
Shorten the long antibiotic treatment against M. tuberculosis
Latent Tuberculosis
Pediatric TB: Tuberculous meningitis

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 How to identify new TB Drugs?
Target-based approaches
Compound screens on molecular targets
Selected based on Omics / Gene Essentiality
Very potent in vitro inhibitors (IC50 < nanomolar)
Lack of potency on the bacterium
Whole cell approaches
Mycobacterial growth inhibitors M. smegmatis, M. tuberculosis
TMC207 (Bedaquiline, Sirturo) Andries et al. 2005
OPC-67683 (Delamanid) Matsumoto et al. 2006
Effect on bacillus growth inside the host
Inside the macrophage
Anti-virulence
HDT: Host Targeted Therapy, Immunotherapy

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 What are the steps for the development of a
novel drug candidate?
Preclinical studies
HTS: high throughput screening
Hit to Lead (H2L)
Preclinical candidate
Clinical phases: PI to PIII

From Payne et al. Nature Drug Discovery reviews, doi:10.1038/nrd2201

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 Which drugs are under development?

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 PBTZ169 – a DprE1 inhibitor
BTZ compounds active on intra/extracellular bacteria
Active on MDR
Target DprE1 (Rv3190): Decaprenylphosphoryl-beta-D-ribose oxidase
in vivo efficacy
PK/PD satisfactory, Phase II by Nearmedic Plus LLC

Makavov et al. 2009, et al. 2014. http://im4tb.org/

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 Q203 – a QcrB inhibitor
IPA compounds active on intra/extracellular bacteria
Active on MDR
Target QcrB (Rv2196): ubiquinol cytochrome C reductase
in vivo efficacy
PK/PD satisfactory, Phase I

MIC intracellular 0.3 nM

MIC extracellular 3 nM Q203

Moraski et al. 2011, Pethe et al,2013; Kang et al. J. Med Chem 2014

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 Spiroisoxazoline SMARt-420 - an EthR2 ligand
BDM compounds are booster of Ethionamide (ETH) activity
Active on MDR and EthA resistant strains
Target EthR2 (Rv2196):
in vivo efficacy in combination with sub-toxic doses of ETH
Preclicinal stage for boosters+ ETH
EthR

Ethionamide/ ETH Resistance

EthA
CH3
H2N
N
S EthA2

N O EthR2
O
N
R

CF3
SMARt-420

Willand et al. 2009, Blondiaux et al. 2017

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 Summary
Success of Phenotypic screening for Lead generation
Identification of novel druggable targets
Numerous candidates in H2L and Lead Optimization

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 THANK YOU for your attention

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