Tuberculosis drug discovery in the post‐post‐genomic era

Lechartier, Benoît; Rybniker, Jan; Zumla, Alimuddin; Cole, Stewart T.

doi:10.1002/emmm.201201772

Cited by 161 publications

(190 citation statements)

References 75 publications

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“…We need innovative combination regimens comprising new molecules able to kill drug-susceptible and drug-resistant strains of M. tuberculosis while simultaneously decreasing treatment duration by targeting active and persistent tubercle bacilli (16).…”

Section: Discussionmentioning

confidence: 99%

Mode of Action of Clofazimine and Combination Therapy with Benzothiazinones against Mycobacterium tuberculosis

Lechartier

Cole

2015

Antimicrob Agents Chemother

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117

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Clofazimine (CZM) is an antileprosy drug that was recently repurposed for treatment of multidrug-resistant tuberculosis. In Mycobacterium tuberculosis, CZM appears to act as a prodrug, which is reduced by NADH dehydrogenase (NDH-2), to release reactive oxygen species upon reoxidation by O 2 . CZM presumably competes with menaquinone (MK-4), a key cofactor in the mycobacterial electron transfer chain, for its reduction by NDH-2. We studied the effect of MK-4 supplementation on the activity of CZM against M. tuberculosis and found direct competition between CZM and MK-4 for the cidal effect of CZM, against nonreplicating and actively growing bacteria, as MK-4 supplementation blocked the drug's activity against nonreplicating bacteria. We demonstrated that CZM, like bedaquiline, is synergistic in vitro with benzothiazinones such as 2-piperazino-benzothiazinone 169 (PBTZ169), and this synergy also occurs against nonreplicating bacteria. The synergy between CZM and PBTZ169 was lost in an MK-4-rich medium, indicating that MK-4 is the probable link between their activities. The efficacy of the dual combination of CZM and PBTZ169 was tested in vivo, where a great reduction in bacterial load was obtained in a murine model of chronic tuberculosis. Taken together, these data confirm the potential of CZM in association with PBTZ169 as the basis for a new regimen against drug-resistant strains of M. tuberculosis. With approximately 9 million incident cases of tuberculosis (TB) worldwide and around 1.5 million deaths in 2012, Mycobacterium tuberculosis infection is one of the most important causes of death from a single infectious agent (1). The spread of multidrug-resistant TB (MDR-TB), namely, with resistance to isoniazid and rifampin, poses additional challenges to treatment with currently available anti-TB drugs. The situation is exacerbated by the increasing emergence of extensively drug-resistant (XDR) strains of M. tuberculosis, which cause diseases essentially untreatable with existing compounds. It is nowadays widely acknowledged that we need to develop new antibiotic combinations for TB and that these new regimens should be tested together at the preclinical stage, rather than testing a series of single drugs separately, in order to fill the TB drug development pipeline more efficiently (2-4).Some of the compounds in advanced clinical trials for TB are molecules that were originally used to treat other infectious diseases and have been repurposed for TB. Among the repurposed molecules, clofazimine (CZM), a riminophenazine originally developed as a drug to treat TB but overlooked for decades, has been used as a standard component of the treatment of leprosy for 50 years. It was recently repurposed for managing MDR-TB cases, notably following the results of the so-called Bangladesh study, which demonstrated that a CZM-containing regimen can cure such resistant cases in 9 to 12 months (5). Grosset et al. demonstrated the substantial benefit of adding CZM to second-line regimens in mice infected with isoniazid-resistant...

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Section: Discussionmentioning

confidence: 99%

Mode of Action of Clofazimine and Combination Therapy with Benzothiazinones against Mycobacterium tuberculosis

Lechartier

Cole

2015

Antimicrob Agents Chemother

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117

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“…The mixture was stirred at r.t. for 2.5 h and quenched by addition of saturated aqueous solution of NH 4 Cl (30 mL). After removal of volatiles in vacuo, the aqueous phase was extracted with EtOAc (5 × 50 mL) and the combined organic layers were dried over Na 2 …”

Section: Resultsmentioning

confidence: 99%

“…The mixture was stirred at −78°C for 16 h, quenched with a saturated aqueous solution of NH 4 Cl (10 mL) and volatiles were removed in vacuo. The aqueous phase was extracted with DCM (3 × 20 mL) and the combined organic layers were dried over Na 2 7-O-Acetyl-1-trimethylsilyl-hept-1-yne 16. Potassium acetate (595 mg, 6.07 mmol, 15 equiv.)…”

Section: Resultsmentioning

confidence: 99%

5′-Methylene-triazole-substituted-aminoribosyl uridines as MraY inhibitors: synthesis, biological evaluation and molecular modeling

et al. 2015

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The straightforward synthesis of 5'-methylene-[1,4]-triazole-substituted aminoribosyl uridines is described. Two families of compounds were synthesized from a unique epoxide which was regioselectively opened by acetylide ions (for compounds II) or azide ions (for compounds III). Sequential diastereoselective glycosylation with a ribosyl fluoride derivative, Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC) with various complementary azide and alkyne partners afforded the targeted compounds after final deprotection. The biological activity of the 16 resulting compounds together with that of 14 previously reported compounds I, lacking the 5' methylene group, was evaluated on the MraY transferase activity. Out of the 30 tested compounds, 18 compounds revealed MraY inhibition with IC 50 ranging from 15 to 150 µM. A molecular modeling study was performed to rationalize the observed structure-activity relationships (SAR), which allowed us to correlate the activity of the most potent compounds with an interaction involving Leu191 of MraY AA . The antibacterial activity was also evaluated and seven compounds exhibited a good activity against Gram-positive bacterial pathogens with MIC ranging from 8 to 32 µg mL −1

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“…Moreover, several candidate molecules are currently in preclinical studies, phase II and III clinical trials (6,7). However, up to date, only a few drugs are capable of effectively killing non-replicating M. tuberculosis, thus allowing TB reactivation (8). Interestingly, we have recently discovered a new series of thienopyrimidine (TP) compounds that kill both replicating and non-replicating bacilli ( Fig.…”

Section: Among Infectious Human Diseases Tuberculosis (Tb)mentioning

confidence: 99%

The Redox State Regulates the Conformation of Rv2466c to Activate the Antitubercular Prodrug TP053

Albesa‐Jové

Comino

Tersa

et al. 2015

Journal of Biological Chemistry

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Rv2466c is a key oxidoreductase that mediates the reductive activation of TP053, a thienopyrimidine derivative that kills replicating and non-replicating Mycobacterium tuberculosis, but whose mode of action remains enigmatic. Rv2466c is a homodimer in which each subunit displays a modular architecture comprising a canonical thioredoxin-fold with a Cys 19 -Pro 20 -Trp 21 -Cys 22 motif, and an insertion consisting of a four ␣-helical bundle and a short ␣-helical hairpin. Strong evidence is provided for dramatic conformational changes during the Rv2466c redox cycle, which are essential for TP053 activity. Strikingly, a new crystal structure of the reduced form of Rv2466c revealed the binding of a C-terminal extension in ␣-helical conformation to a pocket next to the active site cysteine pair at the interface between the thioredoxin domain and the helical insertion domain. The ab initio low-resolution envelopes obtained from small angle x-ray scattering showed that the fully reduced form of Rv2466c adopts a "closed" compact conformation in solution, similar to that observed in the crystal structure. In contrast, the oxidized form of Rv2466c displays an "open" conformation, where tertiary structural changes in the ␣-helical subdomain suffice to account for the observed conformational transitions. Altogether our structural, biochemical, and biophysical data strongly support a model in which the formation of the catalytic disulfide bond upon TP053 reduction triggers local structural changes that open the substrate binding site of Rv2466c allowing the release of the activated, reduced form of TP053. Our studies suggest that similar structural changes might have a functional role in other members of the thioredoxin-fold superfamily. Among infectious human diseases, tuberculosis (TB)3 is the second greatest killer worldwide due to a single infectious agent, and remains a major challenge to human health care. In 2013, there were about 9 million new cases and 1.5 million deaths from TB, with an estimated one-third of the human population carrying a latent infection (1). First-line treatment for drug-susceptible TB requires the administration of a combination of four drugs during a period of 6 months: isoniazid, rifampicin, ethambutol, and pyrazinamide. Lengthy treatment regimens, unpleasant side effects, and patient noncompliance have provided conditions for the generation of multidrug-resistant and extensively drug-resistant cases of TB (2). Thus, the discovery and development of novel anti-TB drugs with bactericidal mechanisms different from those of currently available agents has become an urgent need. In that context, bedaquiline, a diarylquinoline that inhibits the c subunit of ATP synthase from Mycobacterium tuberculosis, has been recently approved by the Food and Drug Administration (FDA) for the treatment of multidrug-resistant TB in adults (3-5). Moreover, several candidate molecules are currently in preclinical studies, phase II and III clinical trials (6, 7). However, up to date, only a few drugs are capable of e...

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Tuberculosis drug discovery in the post‐post‐genomic era

Cited by 161 publications

References 75 publications

Mode of Action of Clofazimine and Combination Therapy with Benzothiazinones against Mycobacterium tuberculosis

Mode of Action of Clofazimine and Combination Therapy with Benzothiazinones against Mycobacterium tuberculosis

5′-Methylene-triazole-substituted-aminoribosyl uridines as MraY inhibitors: synthesis, biological evaluation and molecular modeling

The Redox State Regulates the Conformation of Rv2466c to Activate the Antitubercular Prodrug TP053

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