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Wednesday, August 6, 2025

Diarylquinolines


Diarylquinolines are a novel class of synthetic antimicrobial agents characterized by a unique mechanism of action targeting the mycobacterial ATP synthase enzyme. This class is especially significant in the treatment of multidrug-resistant tuberculosis (MDR-TB) and extensively drug-resistant tuberculosis (XDR-TB). The most prominent and currently approved agent in this class is bedaquiline, which revolutionized MDR-TB therapy by introducing a new mechanism distinct from traditional anti-TB agents.


1. Introduction and Background

Diarylquinolines emerged from efforts to identify novel anti-mycobacterial agents with new targets due to rising resistance to first-line and second-line anti-TB drugs. The class is characterized by:

  • A diarylquinoline core structure, giving the name

  • A specific inhibitory action on proton-translocating mycobacterial ATP synthase, leading to energy depletion in Mycobacterium tuberculosis

  • Selective activity against M. tuberculosis with minimal activity on human mitochondrial ATP synthase, though off-target effects exist

Currently, bedaquiline (Sirturo) is the only FDA- and WHO-approved diarylquinoline.

2. Chemical and Structural Features

  • Bedaquiline is a cationic amphiphilic diarylquinoline compound

  • Molecular structure: features a quinoline moiety and two aromatic rings (diaryl)

  • Highly lipophilic, allowing intracellular accumulation in macrophages, a primary host of M. tuberculosis

3. Mechanism of Action

  • Targets subunit c of the mycobacterial F0 complex of ATP synthase (Rv1305 gene product)

  • Inhibits ATP synthesis → depletion of intracellular ATP → bactericidal activity

  • Uniquely effective against both replicating and non-replicating dormant TB bacilli

This mechanism is not shared by any other class of antitubercular drugs, reducing the likelihood of cross-resistance.

4. Therapeutic Indications

Approved use:

  • Multidrug-resistant tuberculosis (MDR-TB)

  • Extensively drug-resistant tuberculosis (XDR-TB)

  • Pre-XDR TB (TB resistant to rifampin and fluoroquinolones)

Used as part of combination therapy with other antitubercular agents such as linezolid, pretomanid, levofloxacin, clofazimine, and cycloserine.

Off-label/emerging indications:

  • Drug-sensitive TB (under clinical investigation)

  • Nontuberculous mycobacterial infections (NTM) – investigational

5. Pharmacokinetics

PropertyBedaquiline
BioavailabilityEnhanced with high-fat meals (↑ absorption)
Half-lifeTerminal half-life ~5.5 months (extremely long)
Protein binding>99.9% (albumin-bound)
MetabolismCYP3A4 → N-desmethylbedaquiline (active metabolite, but less potent)
EliminationFecal (>90%), negligible renal excretion
Time to peak concentration5–6 hours post-dose


The long half-life means therapeutic drug levels persist for months post-treatment but also raises toxicity concerns with prolonged exposure.

6. Dosage and Administration

Bedaquiline is administered orally as part of a combination regimen:

  • Weeks 1–2: 400 mg once daily

  • Weeks 3–24: 200 mg three times per week (e.g., Monday, Wednesday, Friday)

Duration: 24 weeks (6 months) recommended; extension under clinical discretion.

Administration should be with food to enhance absorption.

7. Adverse Effects

Common Adverse EventsSerious/Notable Toxicities
Nausea, arthralgia, headacheQT prolongation (dose-limiting; requires ECG monitoring)
Elevation of liver enzymesHepatotoxicity (especially with other TB drugs)
Dizziness, rashSudden cardiac death (observed in trials)
Increased uric acid levelsSkeletal muscle toxicity (rare)


QT prolongation is the most clinically significant adverse effect. Bedaquiline may prolong the QTc interval by ~15 ms on average; caution with other QT-prolonging drugs is essential.

8. Contraindications

  • Known hypersensitivity to bedaquiline or excipients

  • Concomitant use with strong CYP3A4 inducers (e.g., rifampin, phenytoin)

  • Congenital long QT syndrome

  • Baseline QTc >450 ms

  • Severe hepatic impairment

9. Drug Interactions

Interacting Drug/ClassInteraction Effect
Rifampin, rifabutin↓ Bedaquiline exposure by up to 80% (CYP3A4 induction) – contraindicated
Ketoconazole, ritonavir↑ Bedaquiline exposure (CYP3A4 inhibition) – caution required
Macrolides (azithromycin, etc.)↑ Risk of QT prolongation – monitor ECG
FluoroquinolonesAdditive QTc effects – ECG monitoring mandatory
Efavirenz (antiretroviral)Reduces bedaquiline levels – avoid or adjust
Alcohol↑ Risk of hepatotoxicity


Co-administration with QT-prolonging drugs demands strict cardiac monitoring with baseline and serial ECGs.

10. Clinical Trials and Efficacy Data

  • Phase IIb (TMC207-C208): Bedaquiline + background regimen significantly improved 24-week culture conversion (79% vs. 58%) in MDR-TB

  • WHO endTB and Nix-TB trials: Validated its role in all-oral regimens for XDR-TB

  • ZeNix Trial (2021): Bedaquiline + linezolid + pretomanid: 89% cure in highly resistant TB

11. Use in Special Populations

Hepatic impairment:

  • Use with caution; not recommended in Child-Pugh C

Renal impairment:

  • No dose adjustment needed in mild/moderate disease

HIV co-infection:

  • Requires careful selection of antiretrovirals due to CYP3A4 interactions

Pediatrics:

  • Approved for ages ≥5 years (weight ≥15 kg), per updated WHO guidance

Pregnancy and Lactation:

  • Category B (limited human data)

  • Used only if benefits outweigh risks

12. Monitoring Parameters

  • Baseline and follow-up ECG: Monitor QTc at baseline, 2, 4, 8, 12, and 24 weeks

  • LFTs: Monthly monitoring of ALT, AST, bilirubin

  • Serum electrolytes: Especially potassium, calcium, magnesium

  • Clinical symptoms: Dizziness, syncope, palpitations (suggestive of arrhythmia)

13. WHO Guidelines and Global Health Use

  • WHO recommends bedaquiline-based regimens as first-line for MDR-TB/XDR-TB

  • Included in Group A drugs in the WHO MDR-TB treatment framework alongside linezolid and fluoroquinolones

  • All-oral regimens are now preferred; injectable agents are avoided unless necessary

  • Included in the Global Drug Facility (GDF) for TB programs

14. Resistance and Limitations

  • Resistance to bedaquiline is emerging due to Rv0678 mutations

  • Cross-resistance with clofazimine via the same efflux pump regulation has been reported

  • Resistance testing is not widely available, but WHO encourages development of molecular assays

15. Pipeline and Future Diarylquinolines

Beyond bedaquiline, other diarylquinolines under development include:

  • TBAJ-876: Potent bedaquiline analogue with reduced QT effects

  • TBAJ-587: Next-generation compound undergoing phase I/II trials

These newer agents aim to overcome resistance and enhance safety by reducing cardiac and hepatic toxicity.



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