Short-course treatment regimen to identify potential antituberculous agents in a murine model of tuberculosis

Shoen, Carolyn; DeStefano, Michelle S.; Sklaney, Mary; Monica, Bobbi J; Slee, Andrew M.; Cynamon, Michael H.

doi:10.1093/jac/dkh124

Cited by 21 publications

(13 citation statements)

References 20 publications

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“…Independent experiments with different donor macrophages showed variable kinetics, with increases up to 12-fold at 2 h postinfection and levels remaining elevated until termination of the experiments. Transcript levels were also elevated in bacteria growing in the lungs of mice in a previously described active-infection model (31), as shown in Table 1. Increased expression of proXVWZ upon interactions with host cells suggested that the encoded transporter might contribute to bacterial adaptation to the environment within phagocytic cells.…”

Section: Vol 190 2008 Betaine and Intracellular M Tuberculosis 3957mentioning

confidence: 74%

“…Total RNA from bacterial mid-log-phase broth cultures, infected primary human MDMs, or frozen mouse lung tissue specimens was isolated using an RNeasy mini kit, following the manufacturer's instructions with minor modifications (Qiagen). Quickfrozen mouse lung tissues were obtained as approved by the Upstate Medical University IACUC from experimentally infected C57BL6 mice 7 days following intranasal infection using a previously described active infection model (31). Samples in Qiagen lysis buffer were first heated at 70°C for 1 min to assist in lysing mycobacteria and then transferred to tubes containing 0.1-mm zirconia silica beads (Biospec) and processed in a Fast-A homogenizer (Bio101) prior to being applied to RNeasy columns.…”

Section: Methodsmentioning

confidence: 99%

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Glycine Betaine Uptake by the ProXVWZ ABC Transporter Contributes to the Ability ofMycobacterium tuberculosisTo Initiate Growth in Human Macrophages

Price¹,

Bukka²,

Cynamon

et al. 2008

J Bacteriol

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Mycobacterium tuberculosis maintains a large genetic capacity necessary for growth in different environments during infection and survival upon aerosol transmission to new hosts. Screening for bacterial RNAs produced in response to host interactions produced candidate lists where we noted proXVWZ, annotated as encoding a putative glycine betaine or proline transporter. As high surface-to-volume ratios make bacterial cells particularly vulnerable to changes in water availability, we investigated the contributions of this transporter to the ability of M. tuberculosis to colonize macrophages. An H37Rv proXVWZ mutant was impaired for initial survival and intracellular growth and exhibited reduced growth at elevated medium osmolarity. This defect could be complemented by restoring proXVWZ and was attributable to a failure to accumulate the compatible solute glycine betaine. We then demonstrated that ProXVWZ allows M. tuberculosis to obtain betaine from host macrophages and thereby contributes to early steps in colonizing this niche.

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Section: Vol 190 2008 Betaine and Intracellular M Tuberculosis 3957mentioning

confidence: 74%

Section: Methodsmentioning

confidence: 99%

Glycine Betaine Uptake by the ProXVWZ ABC Transporter Contributes to the Ability ofMycobacterium tuberculosisTo Initiate Growth in Human Macrophages

Price¹,

Bukka²,

Cynamon

et al. 2008

J Bacteriol

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“…All animal procedures were approved by the Institutional Animal Care and Use Committee (Johns Hopkins University) or the Subcommittee for Animal Studies (SAS; Central New York Research Corporation). Aerosol and intranasal infections were performed as previously described (22,23). Mycobacterial stocks were stored frozen at Ϫ70°C until use, and on the day of infection, the culture was thawed and sonicated.…”

Section: Methodsmentioning

confidence: 99%

A Novel Inhibitor of Gyrase B Is a Potent Drug Candidate for Treatment of Tuberculosis and Nontuberculosis Mycobacterial Infections

Locher

Jones

Hanzelka

et al. 2015

Antimicrob Agents Chemother

101

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dNew drugs to treat drug-resistant tuberculosis are urgently needed. Extensively drug-resistant and probably the totally drugresistant tuberculosis strains are resistant to fluoroquinolones like moxifloxacin, which target gyrase A, and most people infected with these strains die within a year. In this study, we found that a novel aminobenzimidazole, VXc-486, which targets gyrase B, potently inhibits multiple drug-sensitive isolates and drug-resistant isolates of Mycobacterium tuberculosis in vitro (MICs of 0.03 to 0.30 g/ml and 0.08 to 5.48 g/ml, respectively) and reduces mycobacterial burdens in lungs of infected mice in vivo. VXc-486 is active against drug-resistant isolates, has bactericidal activity, and kills intracellular and dormant M. tuberculosis bacteria in a low-oxygen environment. Furthermore, we found that VXc-486 inhibits the growth of multiple strains of Mycobacterium abscessus, Mycobacterium avium complex, and Mycobacterium kansasii (MICs of 0.1 to 2.0 g/ml), as well as that of several strains of Nocardia spp. (MICs of 0.1 to 1.0 g/ml). We made a direct comparison of the parent compound VXc-486 and a phosphate prodrug of VXc-486 and showed that the prodrug of VXc-486 had more potent killing of M. tuberculosis than did VXc-486 in vivo. In combination with other antimycobacterial drugs, the prodrug of VXc-486 sterilized M. tuberculosis infection when combined with rifapentine-pyrazinamide and bedaquiline-pyrazinamide in a relapse infection study in mice. Furthermore, the prodrug of VXc-486 appeared to perform at least as well as the gyrase A inhibitor moxifloxacin. These findings warrant further development of the prodrug of VXc-486 for the treatment of tuberculosis and nontuberculosis mycobacterial infections.

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“…Mice are relevant species as they have been used as an animal model for testing the in vivo efficacy of antituberculosis drugs [Chambers et al, 2005;Davies et al, 2007;Gangadharam et al, 1999;Nuermberger, 2008;Shoen et al, 2004;Williams et al, 2009].…”

Section: Discussionmentioning

confidence: 99%

Effects of isatin‐isoniazid derivatives on drug metabolizing and chemoprotective enzymes in mice

El‐Sayed

Aboul‐Fadl

Franklin

2010

Drug Development Research

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Four isatin-isoniazid derivatives with proven efficacy against resistant strains of Mycobacterium tuberculosis, that had greater lipophilicity than isoniazid were evaluated for effects on hepatic drug metabolizing and chemoprotective enzymes and compared to isoniazid. Following intragastric administration to mice (75 or 150 mg/kg Â 3 days), none of the four compounds exhibited hepatotoxicity, and only isoniazid was found to elevate CYP2E1 activity. All compounds slightly elevated Cyp1a1/2 mRNA levels, but these did not result in increased methoxyresorufin demethylase activity. With the exception of isoniazid, approximately twofold elevations in Ugt1a mRNAs (seen with isatin-isoniazid [Ugt1a1, Ugt1a6, Ugt1a9], 1-propynylisatin-isoniazid [Ugt1a1, Ugt1a9], and 1-propylisatin-isoniazid [Ugt1a1]) also did not result in changes in 4-nitrophenol glucuronidation activity. 1-Benzylisatin-isoniazid was the only compound that (1) elevated Ugt2b5 mRNA, and (2) like isoniazid, had no effect on glutathione transferase activities and mRNAs. 1-Propynylisatin-isoniazid elevated glutathione transferase activity toward 1-chloro-2,4-dinitrobenzene, 1-propylisatin-isoniazid decreased the 2.4-kb Gstp transcript, and isatin-isoniazid increased Gsta, Gstm, and the 1.2-kb Gstp transcripts. None of the four compounds affected glutathione peroxidase activity, although 1-propynylisatin-isoniazid and 1-benzylisatin-isoniazid elevated mRNA transcripts. None of the four compounds affected microsomal epoxide hydrolase or thioredoxin reductase activities but, in parallel, isoniazid, 1-propynylisatin-isoniazid, and 1-propylisatin-isoniazid elevated mRNAs of each. 1-Propynylisatin-isoniazid, 1-propylisatin-isoniazid, and 1-benzylisatin-isoniazid, and isoniazid, elevated quinone oxidoreductase (Nqo1) mRNA, but only 1-propylisatin-isoniazid elevated the activity. Altogether, and despite some changes in mRNA expression, the novel isatin-isoniazid derivatives had only minor effects on mouse hepatic enzyme activities and are worthy of further investigation as possible therapeutic agents likely free of major induction-related drug-drug interactions. Drug Dev Res 71:313-322, 2010.

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Short-course treatment regimen to identify potential antituberculous agents in a murine model of tuberculosis

Abstract: Use of this model to screen potential chemotherapeutic agents will save time and resources.

Cited by 21 publications

References 20 publications

Glycine Betaine Uptake by the ProXVWZ ABC Transporter Contributes to the Ability ofMycobacterium tuberculosisTo Initiate Growth in Human Macrophages

Glycine Betaine Uptake by the ProXVWZ ABC Transporter Contributes to the Ability ofMycobacterium tuberculosisTo Initiate Growth in Human Macrophages

A Novel Inhibitor of Gyrase B Is a Potent Drug Candidate for Treatment of Tuberculosis and Nontuberculosis Mycobacterial Infections

Effects of isatin‐isoniazid derivatives on drug metabolizing and chemoprotective enzymes in mice

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