Antitubercular Agents

Aldrich, Courtney C.; Boshoff, Helena I.

doi:10.1002/0471266949.bmc231

Cited by 10 publications

(10 citation statements)

References 626 publications

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“…The development of new antibiotics for TB has traditionally been performed by empirically screening compound collections and natural product extracts for in vitro antitubercular whole-cell activity without any a priori knowledge of their mechanism-of-action (MOA) (Aldrich, et al, 2010; Marriner, et al, 2011). Streptomycin, the very first antibiotic effective against Mtb discovered by Albert Schatz in Selman Waksman’s laboratory at Rutgers in 1943, and bedaquiline, the newest TB drug developed by Koen Andries’ team at Janssen Pharmaceuticals and approved by the FDA for multidrug resistant-TB in 2012, were discovered in this manner (Andries, et al, 2005; Schatz, et al, 1944).…”

Section: Introductionmentioning

confidence: 99%

Target-Based Identification of Whole-Cell Active Inhibitors of Biotin Biosynthesis in Mycobacterium tuberculosis

Park

Casalena

Wilson

et al. 2015

Chemistry & Biology

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SUMMARY Biotin biosynthesis is essential for survival and persistence of Mycobacterium tuberculosis (Mtb) in vivo. The aminotransferase BioA, which catalyzes the antepenultimate step in the biotin pathway, has been established as a promising target due to its vulnerability to chemical inhibition. We performed high-throughput screening (HTS) employing a fluorescence displacement assay and identified a diverse set of potent inhibitors including many diversity-oriented synthesis (DOS) scaffolds. To efficiently select only hits targeting biotin biosynthesis, we then deployed a whole-cell counter-screen in either biotin-free and biotin-containing medium against wild-type Mtb and in parallel with isogenic bioA Mtb strains that possess differential levels of BioA expression. This counter-screen proved crucial to filter out compounds whose whole-cell activity was off-target as well as identify hits with weak, but measurable whole-cell activity in BioA-depleted strains. Several of the most promising hits were co-crystallized with BioA to provide a framework for future structure-based drug design efforts.

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Section: Introductionmentioning

confidence: 99%

Target-Based Identification of Whole-Cell Active Inhibitors of Biotin Biosynthesis in Mycobacterium tuberculosis

Park

Casalena

Wilson

et al. 2015

Chemistry & Biology

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“…3 Indeed the discovery of other TB drugs followed in rapid succession with para -aminosalicylic acid (1946), pyrazinamide (1952), isoniazid (1952), ethambutol (1961), and rifampin (1965), among many others. 4 Introduction of these antibiotics led to a staggering drop in TB incidence in the developing world.…”

Section: Introductionmentioning

confidence: 99%

Structure–activity relationships of 2-aminothiazoles effective against Mycobacterium tuberculosis

Meißner

Boshoff

Vasan

et al. 2013

Bioorganic & Medicinal Chemistry

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A series of 2-aminothiazoles was synthesized based on a HTS scaffold from a whole-cell screen against Mycobacterium tuberculosis (Mtb). The SAR shows the central thiazole moiety and the 2-pyridyl moiety at C-4 of the thiazole are intolerant to modification. However, the N-2 position of the aminothiazole exhibits high flexibility and we successfully improved the antitubercular activity of the initial hit by more than 128-fold through introduction of substituted benzoyl groups at this position. N-(3-Chlorobenzoyl)-4-(2-pyridinyl)-1,3-thiazol-2-amine (55) emerged as one of the most promising analogues with a MIC of 0.024 μM or 0.008 μg/mL in 7H9 media and therapeutic index of nearly ~300. However, 55 is rapidly metabolized by human liver microsomes (t1/2 = 28 min) with metabolism occurring at the invariant aminothiazole moiety and Mtb develops spontaneous resistance with a high frequency of ~10−5.

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“…This latter compound was first commercialized with the name of Aldinamide by Lederle Laboratories (American Cyanamid, Wayne, NY, USA) for the treatment of Mycobacterium tuberculosis infections. In combination with isoniazid (INH) and rifampin, PZA allowed the conventional 9-month tuberculosis treatment regimen to be shortened to 4–6 months (Aldrich et al, 2010). This pro-drug is converted into POA by Mycobacterium tuberculosis nicotinamidase (Kalinda and Aldrich, 2012).…”

Section: Discussionmentioning

confidence: 99%

Combined Whole-Cell High-Throughput Functional Screening for Identification of New Nicotinamidases/Pyrazinamidases in Metagenomic/Polygenomic Libraries

et al. 2016

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Nicotinamidases catalyze the hydrolysis of the amide bond in nicotinamide (NAM) to produce ammonia and nicotinic acid (NA). These enzymes are an essential component of the NAD+ salvage pathway and are implicated in the viability of several pathogenic organisms. Its absence in humans makes them a promising drug target. In addition, although they are key analytical biocatalysts for screening modulators in relevant biomedical enzymes, such as sirtuins and poly-ADP-ribosyltransferases, no commercial sources are available. Surprisingly, the finding of an affordable source of nicotinamidase from metagenomic libraries is hindered by the absence of a suitable and fast screening method. In this manuscript, we describe the development of two new whole-cell methods using the chemical property of one of the products formed in the enzymatic reaction (pyrazinoic or NA) to form colored complexes with stable iron salts, such as ammonium ferrous sulfate or sodium nitroprusside (SNP). After optimization of the assay conditions, a fosmid polygenomic expression library obtained from deep-sea mesophilic bacteria was screened, discovering several positive clones with the ammonium ferrous sulfate method. Their quantitative rescreening with the SNP method allowed the finding of the first nicotinamidase with balanced catalytic efficiency toward NAM (nicotinamidase activity) and pyrazinamide (pyrazinamidase activity). Its biochemical characterization has also made possible the development of the first high-throughput whole-cell method for prescreening of new nicotinamidase inhibitors by the naked eye, saving time and costs in the design of future antimicrobial and antiparasitic agents.

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Antitubercular Agents

Cited by 10 publications

References 626 publications

Target-Based Identification of Whole-Cell Active Inhibitors of Biotin Biosynthesis in Mycobacterium tuberculosis

Target-Based Identification of Whole-Cell Active Inhibitors of Biotin Biosynthesis in Mycobacterium tuberculosis

Structure–activity relationships of 2-aminothiazoles effective against Mycobacterium tuberculosis

Combined Whole-Cell High-Throughput Functional Screening for Identification of New Nicotinamidases/Pyrazinamidases in Metagenomic/Polygenomic Libraries

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