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Item Design, synthesis, and evaluation of substituted nicotinamide adenine dinucleotide (NAD+) synthetase inhibitors as potential antitubercular agents(Elsevier, 2017-09-15) Wang, Xu; Ahn, Yong-Mo; Lentscher, Adam G.; Lister, Julia S.; Brothers, Robert C.; Kneen, Malea M.; Gerratana, Barbara; Boshoff, Helena I.; Dowd, Cynthia S.; Chemistry and Chemical Biology, School of ScienceNicotinamide adenine dinucleotide (NAD+) synthetase catalyzes the last step in NAD+ biosynthesis. Depletion of NAD+ is bactericidal for both active and dormant Mycobacterium tuberculosis (Mtb). By inhibiting NAD+ synthetase (NadE) from Mtb, we expect to eliminate NAD+ production which will result in cell death in both growing and nonreplicating Mtb. NadE inhibitors have been investigated against various pathogens, but few have been tested against Mtb. Here, we report on the expansion of a series of urea-sulfonamides, previously reported by Brouillette et al. Guided by docking studies, substituents on a terminal phenyl ring were varied to understand the structure-activity-relationships of substituents on this position. Compounds were tested as inhibitors of both recombinant Mtb NadE and Mtb whole cells. While the parent compound displayed very weak inhibition against Mtb NadE (IC50=1000µM), we observed up to a 10-fold enhancement in potency after optimization. Replacement of the 3,4-dichloro group on the phenyl ring of the parent compound with 4-nitro yielded 4f, the most potent compound of the series with an IC50 value of 90µM against Mtb NadE. Our modeling results show that these urea-sulfonamides potentially bind to the intramolecular ammonia tunnel, which transports ammonia from the glutaminase domain to the active site of the enzyme. This hypothesis is supported by data showing that, even when treated with potent inhibitors, NadE catalysis is restored when treated with exogenous ammonia. Most of these compounds also inhibited Mtb cell growth with MIC values of 19-100µg/mL. These results improve our understanding of the SAR of the urea-sulfonamides, their mechanism of binding to the enzyme, and of Mtb NadE as a potential antitubercular drug target.Item Dormant Mycobacterium tuberculosis converts isoniazid to the active drug in a Wayne’s model of dormancy(Nature, 2018) Raghunandanan, Sajith; Jose, Leny; Kumar, Ramakrishnan Ajay; Dermatology, School of MedicineIsoniazid (INH) is one among the four first-line drugs used in the treatment of tuberculosis. The bactericidal activity of INH is due to its ability to inhibit mycolic acid synthesis, which is an integral component of the mycobacterial cell wall. Non-replicating Mycobacterium tuberculosis (MTB) is phenotypically resistant to INH. The exact mechanism of this resistance is not clear, although the inability of dormant MTB to convert the pro-drug into an active form is thought to be one of the possible reasons. Employing targeted metabolomics approach, we show that dormant MTB can metabolize INH into its active INH-NAD+ adduct form. Further we show that the dormant bacteria have unaltered gene expression levels of katG and inhA (INH metabolizing enzymes). Transcript levels of drug efflux pump proteins which were low during dormancy did not increase in response to INH treatment. These findings point to an alternative mechanism for INH resistance in dormant MTB, which needs to be further elucidated.Item Dual-targeting GroEL/ES chaperonin and protein tyrosine phosphatase B (PtpB) inhibitors: A polypharmacology strategy for treating Mycobacterium tuberculosis infections(Elsevier, 2019-07-01) Washburn, Alex; Abdeen, Sanofar; Ovechkina, Yulia; Ray, Anne-Marie; Stevens, Mckayla; Chitre, Siddhi; Sivinski, Jared; Park, Yangshin; Johnson, James; Hoang; Hoang, Quyen Q.; Chapman, Eli; Parish, Tanya; Johnson, Steven M.; Biochemistry and Molecular Biology, School of MedicineCurrent treatments for Mycobacterium tuberculosis infections require long and complicated regimens that can lead to patient non-compliance, increasing incidences of antibiotic-resistant strains, and lack of efficacy against latent stages of disease. Thus, new therapeutics are needed to improve tuberculosis standard of care. One strategy is to target protein homeostasis pathways by inhibiting molecular chaperones such as GroEL/ES (HSP60/10) chaperonin systems. M. tuberculosis has two GroEL homologs: GroEL1 is not essential but is important for cytokine-dependent granuloma formation, while GroEL2 is essential for survival and likely functions as the canonical housekeeping chaperonin for folding proteins. Another strategy is to target the protein tyrosine phosphatase B (PtpB) virulence factor that M. tuberculosis secretes into host cells to help evade immune responses. In the present study, we have identified a series of GroEL/ES inhibitors that inhibit M. tuberculosis growth in liquid culture and biochemical function of PtpB in vitro. With further optimization, such dual-targeting GroEL/ES and PtpB inhibitors could be effective against all stages of tuberculosis – actively replicating bacteria, bacteria evading host cell immune responses, and granuloma formation in latent disease – which would be a significant advance to augment current therapeutics that primarily target actively replicating bacteria.Item Symptomatic central nervous system tuberculoma, a case report in the United States and literature review(Elsevier, 2019-06-25) Mohammadian, Mahsa; Butt, Saira; Medicine, School of MedicineIntracranial tuberculoma is one of the rare central nervous system manifestations of Mycobacterium tuberculosis (MTB), seen in only 1% of tuberculosis patients. It can manifest as single or multiple lesions, most commonly located in the frontal and parietal lobes. Clinical features are similar to any space-occupying lesion in the brain and can present in the absence of MTB symptoms in other parts of the body. In this article, a 69-year-old immunocompetent man, with history of treated latent tuberculosis infection (LTBI) was reported. He presented with multiple joint arthralgias, weight loss, odd behavior, forgetfulness, intermittent fevers and syncope. Brain imaging revealed numerous enhancing intra-parenchymal lesions in cerebral and cerebellar hemispheres. Patient was successfully treated with anti-tuberculosis medications and corticosteroids, with clinical improvement on future follow ups. High clinical suspicion for tuberculoma as a differential diagnosis of any brain lesion, even in immunocompetent patients in low MTB prevalence countries, can result in early diagnosis and successful clinical outcomes.