Pentacyclic Nitrofurans with In Vivo Efficacy and Activity against Nonreplicating Mycobacterium tuberculosis

Rakesh,; Bruhn, David F.; Scherman, Michael S.; Woolhiser, Lisa K.; Madhura, Dora B.; Maddox, Marcus M.; Singh, Anumeha; Lee, Robin B.; Hurdle, Julian G.; McNeil, Michael; Lenaerts, Anne J.; Meibohm, Bernd; Lee, Richard

doi:10.1371/journal.pone.0087909

Cited by 24 publications

(16 citation statements)

References 37 publications

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“…In vitro synergy was assessed using M. tuberculosis strain H37Rv, which was cultured as described previously 17 . Fractional inhibitory concentration index (FICI) scores were calculated as described 18 .…”

Section: Methodsmentioning

confidence: 99%

Spectinamides are effective partner agents for the treatment of tuberculosis in multiple mouse infection models

Robertson

Scherman

Bruhn

et al. 2016

J. Antimicrob. Chemother.

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Objectives: New drug regimens employing combinations of existing and experimental antimicrobial agents are needed to shorten treatment of tuberculosis (TB) in humans. The spectinamides are narrow-spectrum semisynthetic analogues of spectinomycin, modified to avoid intrinsic efflux by Mycobacterium tuberculosis. Spectinamides, including lead 1599, have been previously shown to exhibit a promising therapeutic profile in mice as single agents. Here we explore the in vivo activity of lead spectinamides when combined with other agents. Methods: The efficacy of 1599 or 1810 was tested in combination in three increasingly advanced TB mouse models. Mice were infected by aerosol and allowed to establish acute or chronic infection, followed by treatment (≤4 weeks) with the spectinamides alone or in two- and three-drug combination regimens with existing and novel therapeutic agents. Bacteria were enumerated from lungs by plating for cfu. Results: Herein we show the following: (i) 1599 exhibits additive or synergistic activity with most of the first-line agents; (ii) 1599 in combination with rifampicin and pyrazinamide or with bedaquiline and pyrazinamide promotes significantly improved efficacy in the high-dose aerosol model; (iii) 1599 enhances efficacy of rifampicin or pyrazinamide in chronically infected BALB/c mice; and (iv) 1599 is synergistic when administered in combination with rifampicin and pyrazinamide in the C3HeB/FeJ mouse model showing caseous necrotic pulmonary lesions. Conclusions: Spectinamides were effective partner agents for multiple anti-TB agents including bedaquiline, rifampicin and pyrazinamide. None of these in vivo synergistic interactions was predicted from in vitro MIC chequerboard assays. These data support further development of the spectinamides as combination partners with existing and experimental anti-TB agents.

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Section: Methodsmentioning

confidence: 99%

Spectinamides are effective partner agents for the treatment of tuberculosis in multiple mouse infection models

Robertson

Scherman

Bruhn

et al. 2016

J. Antimicrob. Chemother.

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“…Examples of nitro-containing molecules that kill nonreplicating mycobacteria include metronidazole (19,159,161,259) (264).…”

Section: Multiple Physiological Stressesmentioning

confidence: 99%

Targeting Phenotypically TolerantMycobacterium tuberculosis

Gold

Nathan

2017

Tuberculosis and the Tubercle Bacillus

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While the immune system is credited with averting tuberculosis in billions of individuals exposed to Mycobacterium tuberculosis, the immune system is also culpable for tempering the ability of antibiotics to deliver swift and durable cure of disease. In individuals afflicted with tuberculosis, host immunity produces diverse microenvironmental niches that support suboptimal growth, or complete growth arrest, of M. tuberculosis. The physiological state of nonreplication in bacteria is associated with phenotypic drug tolerance. Many of these host microenvironments, when modeled in vitro by carbon starvation, complete nutrient starvation, stationary phase, acidic pH, reactive nitrogen intermediates, hypoxia, biofilms, and withholding streptomycin from the streptomycinaddicted strain SS18b, render M. tuberculosis profoundly tolerant to many of the antibiotics that are given to tuberculosis patients in a clinical setting. Targeting nonreplicating persisters is anticipated to reduce the duration of antibiotic treatment and rate of post-treatment relapse. Some promising drugs to treat tuberculosis, such as rifampicin and bedaquiline, only kill nonreplicating M. tuberculosis in vitro at concentrations far greater than their minimal inhibitory concentrations against replicating bacilli. There is an urgent demand to identify which of the currently used antibiotics, and which of the molecules in academic and corporate screening collections, have potent bactericidal action on nonreplicating M. tuberculosis. With this goal, we review methods of high throughput screening to target nonreplicating M. tuberculosis and methods to progress candidate molecules. A classification based on structures and putative targets of molecules that have been reported to kill nonreplicating M. tuberculosis revealed a rich diversity in pharmacophores. However, few of these compounds were tested under conditions that would exclude the impact of adsorbed compound acting during the recovery phase of the assay, and few were tested under more than one condition imposing nonreplication. That nonreplicating mycobacteria are metabolically active was corroborated by their susceptibility to several antibiotics and tool compounds that target the synthesis of lipids, RNA, DNA, proteins, and peptidoglycan.

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“…Examples of nitro-containing molecules that kill nonreplicating mycobacteria include metronidazole (19, 159, 161, 259); furaltadone ( compound 75 ) (259); nitrofurantoin ( compound 76 ) (96, 259); nitrofurazone ( compound 77 ) (259); furazolidone ( compound 78 ) (96); nitazoxanide ( compound 79 ) (34, 50, 260); niclosamide ( compound 80 ) (96); compound 9 (113); nitrofuranylcalanolide ( compound 81 ) (134); OPC-67683 ( compound 82 ) (261, 262); PA-824 (50, 51, 96, 132, 152, 160, 263); TBA-354 ( compound 83 ) (262); and compound 84 (264). …”

Section: Class II Persisters: a Majority Population Of Nonreplicatmentioning

confidence: 99%

Targeting Phenotypically TolerantMycobacterium tuberculosis

2017

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While the immune system is credited with averting tuberculosis in billions of individuals exposed to Mycobacterium tuberculosis, the immune system is also culpable for tempering the ability of antibiotics to deliver swift and durable cure of disease. In individuals afflicted with tuberculosis, host immunity produces diverse microenvironmental niches that support suboptimal growth, or complete growth arrest, of M. tuberculosis. The physiological state of nonreplication in bacteria is associated with phenotypic drug tolerance. Many of these host microenvironments, when modeled in vitro by carbon starvation, complete nutrient starvation, stationary phase, acidic pH, reactive nitrogen intermediates, hypoxia, biofilms, and withholding streptomycin from the streptomycin-addicted strain SS18b, render M. tuberculosis profoundly tolerant to many of the antibiotics that are given to tuberculosis patients in a clinical setting. Targeting nonreplicating persisters is anticipated to reduce the duration of antibiotic treatment and rate of post-treatment relapse. Some promising drugs to treat tuberculosis, such as rifampicin and bedaquiline, only kill nonreplicating M. tuberculosis in vitro at concentrations far greater than their minimal inhibitory concentrations against replicating bacilli. There is an urgent demand to identify which of the currently used antibiotics, and which of the molecules in academic and corporate screening collections, have potent bactericidal action on nonreplicating M. tuberculosis. With this goal, we review methods of high throughput screening to target nonreplicating M. tuberculosis and methods to progress candidate molecules. A classification based on structures and putative targets of molecules that have been reported to kill nonreplicating M. tuberculosis revealed a rich diversity in pharmacophores. However, few of these compounds were tested under conditions that would exclude the impact of adsorbed compound acting during the recovery phase of the assay, and few were tested under more than one condition imposing nonreplication. That nonreplicating mycobacteria are metabolically active was corroborated by their susceptibility to several antibiotics and tool compounds that target the synthesis of lipids, RNA, DNA, proteins, and peptidoglycan.

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Pentacyclic Nitrofurans with In Vivo Efficacy and Activity against Nonreplicating Mycobacterium tuberculosis

Cited by 24 publications

References 37 publications

Spectinamides are effective partner agents for the treatment of tuberculosis in multiple mouse infection models

Spectinamides are effective partner agents for the treatment of tuberculosis in multiple mouse infection models

Targeting Phenotypically TolerantMycobacterium tuberculosis

Targeting Phenotypically TolerantMycobacterium tuberculosis

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