Mechanism of Action of 5-Nitrothiophenes against Mycobacterium tuberculosis

Hartkoorn, Ruben C.; Ryabova, O. B.; Chiarelli, Laurent R.; Riccardi, Giovanna; Makarov, Vadim; Cole, Stewart T.

doi:10.1128/aac.02693-13

Cited by 30 publications

(32 citation statements)

References 17 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Using whole-genome sequencing, we identified a frameshift mutation that resulted in the inactivation of FbiB, an enzyme involved in F 420 biosynthesis in resistant strains, and complementation with functional FbiB restored its susceptibility to 5NP. These findings confirm that the depletion of F 420 is associated with resistance to 5NP, as has also been reported in the case of 5-nitrothiophenes and bicyclic nitroimidazoles (13,14,29). The mechanism was unequivocally confirmed by PA-824 cross-resistance studies using M. tuberculosis strains harboring mutations in either FGD-1 or F 420 biosynthetic enzymes (13).…”

Section: Discussionsupporting

confidence: 86%

“…F 420 (8-hydroxy-5-deazaflavin), a two-electron transfer cofactor, has been implicated in redox balance, methane biosynthesis, and activation of bicyclic nitroimidazoles (26)(27)(28). Mycobacterial strains deficient in F 420 biosynthesis are also resistant to other nitro group-containing drugs, such as 5-nitrothiophenes and bicyclic nitroimidazoles (13,14,29). Therefore, we next investigated whether our resistant strains were also resistant to killing by PA-824, a bicyclic nitroimidazole, and observed that they were resistant to killing by PA-824 (Table 3).…”

mentioning

confidence: 99%

See 1 more Smart Citation

Dual Mechanism of Action of 5-Nitro-1,10-Phenanthroline against Mycobacterium tuberculosis

Kidwai

Park

Mawatwal

et al. 2017

Antimicrob Agents Chemother

View full text Add to dashboard Cite

New chemotherapeutic agents with novel mechanisms of action are urgently required to combat the challenge imposed by the emergence of drug-resistant mycobacteria. In this study, a phenotypic whole-cell screen identified 5-nitro-1,10-phenanthroline (5NP) as a lead compound. 5NP-resistant isolates harbored mutations that were mapped to and were also resistant to the bicyclic nitroimidazole PA-824. Mechanistic studies confirmed that 5NP is activated in an F-dependent manner, resulting in the formation of 1,10-phenanthroline and 1,10-phenanthrolin-5-amine as major metabolites in bacteria. Interestingly, 5NP also killed naturally resistant intracellular bacteria by inducing autophagy in macrophages. Structure-activity relationship studies revealed the essentiality of the nitro group for activity, and an analog, 3-methyl-6-nitro-1,10-phenanthroline, that had improved activity and efficacy in mice compared with that of 5NP was designed. These findings demonstrate that, in addition to a direct mechanism of action against, 5NP also modulates the host machinery to kill intracellular pathogens.

show abstract

Section: Discussionsupporting

confidence: 86%

mentioning

confidence: 99%

Dual Mechanism of Action of 5-Nitro-1,10-Phenanthroline against Mycobacterium tuberculosis

Kidwai

Park

Mawatwal

et al. 2017

Antimicrob Agents Chemother

View full text Add to dashboard Cite

show abstract

“…Mutations have been identified in fgd1 and ddn [57,62,63], with cross-resistance to 5-nitrothiophenes (a tuberculostatic compound) [64] as well as delamanid [53]. With minimal inhibitory concentration (MIC) around 0.15-0.3 μg·mL −1 [58,63], the activity of PA-824 is comparable to a combination of isoniazid and rifampicin in the continuation phase of a murine drug model [61].…”

Section: Pa-824 ( Pretomanid)mentioning

confidence: 95%

Novel drugs against tuberculosis: a clinician's perspective

et al. 2014

View full text Add to dashboard Cite

The United Nations Millennium Development Goal of reversing the global spread of tuberculosis by 2015 has been offset by the rampant re-emergence of drug-resistant tuberculosis, in particular fluoroquinolone-resistant multidrug-resistant and extensively drug-resistant tuberculosis. After decades of quiescence in the development of antituberculosis medications, bedaquiline and delamanid have been conditionally approved for the treatment of drug-resistant tuberculosis, while several other novel compounds (AZD5847, PA-824, SQ109 and sutezolid) have been evaluated in phase II clinical trials. Before novel drugs can find their place in the battle against drug-resistant tuberculosis, linezolid has been compassionately used with success in the treatment of fluoroquinolone-resistant multidrug-resistant tuberculosis. This review largely discusses six novel drugs that have been evaluated in phase II and III clinical trials, with focus on the clinical evidence for efficacy and safety, potential drug interactions, and prospect for using multiple novel drugs in new regimens. @ERSpublications A review of the efficacy, safety, and potential of new drugs to improve TB therapy from the perspective of clinicians

show abstract

“…The most commonly used models for nonreplicating mycobacteria are: hypoxia (the “Wayne model”) and the “low oxygen recovery assay” (“LORA”) (29, 95, 96); carbon starvation (54, 122); nutrient starvation (12, 52); stationary phase (105); maintenance of intrabacterial pH under acidic culture conditions (120, 123–127); biofilms (102, 128–131); depleting strain SS18b of streptomycin (103, 104, 132, 133); and a multi-stress model that combines acidic pH (pH 5.0), mild hypoxia (1% O 2 ), nitric oxide and other reactive nitrogen intermediates (0.5 mM NaNO 2 ), and a fatty acid carbon source (0.05% butyrate) (53, 94, 100, 134, 135). There are variations of these models, including an “acidic Wayne model” that combines hypoxia with mild acidity (131), and a nutrient-poor, multi-stress model in which cells are cultured at low pH (pH 5.0) under mild hypoxia or tissue-level normoxia (5% O 2 ) and supra-physiologic levels of CO 2 (10% CO 2 ) (136).…”

Section: Class II Persisters: a Majority Population Of Nonreplicatmentioning

confidence: 99%

Targeting Phenotypically TolerantMycobacterium tuberculosis

2017

View full text Add to dashboard Cite

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.

show abstract

Mechanism of Action of 5-Nitrothiophenes against Mycobacterium tuberculosis

Cited by 30 publications

References 17 publications

Dual Mechanism of Action of 5-Nitro-1,10-Phenanthroline against Mycobacterium tuberculosis

Dual Mechanism of Action of 5-Nitro-1,10-Phenanthroline against Mycobacterium tuberculosis

Novel drugs against tuberculosis: a clinician's perspective

Targeting Phenotypically TolerantMycobacterium tuberculosis

Contact Info

Product

Resources

About