Synthetic EthR inhibitors boost antituberculous activity of ethionamide

Willand, Nicolas; Dirié, Bertrand; Carette, Xavier; Bifani, Pablo; Singhal, Amit; Desroses, Matthieu; Leroux, Florence; Willery, Eve; Mathys, Vanessa; Déprez-Poulain, Rébecca; Delcroix, Guy; Frénois, Fredéric; Aumercier, Marc; Locht, Camille; Villeret, Vincent; Déprez, Benoît; Baulard, Alain R.

doi:10.1038/nm.1950

Cited by 162 publications

(223 citation statements)

References 39 publications

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“…The combination allows β-lactams to kill otherwise refractory bacteria, including M. tuberculosis (28). Similarly, compounds that inhibit the transcriptional repressor EthR enhance the activity of ethionamide against M. tuberculosis via increased expression of ethA, encoding a monooxygenase that activates ethionamide (29).…”

Section: Discussionmentioning

confidence: 99%

Mycobacterium tuberculosis persistence mutants identified by screening in isoniazid-treated mice

Dhar

McKinney

2010

Proc. Natl. Acad. Sci. U.S.A.

113

106

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Tuberculosis (TB) is notoriously difficult to cure, requiring administration of multiple antibiotics for 6 mo or longer. Conventional anti-TB drugs inhibit biosynthetic processes involved in cell growth and division, such as DNA replication, RNA transcription, protein translation, and cell wall biogenesis. Although highly effective against bacteria cultured in vitro under optimal growth conditions, these antibiotics are less effective against bacteria grown in vivo in the tissues of a mammalian host. The factors that contribute to the antibiotic tolerance of bacteria grown in vivo are unknown, although altered metabolism and sluggish growth are hypothesized to play a role. To address this question, we identified mutations in Mycobacterium tuberculosis that impaired or enhanced persistence in mice treated with isoniazid (INH), a front-line anti-TB drug. Disruption of cydC, encoding a putative ATP-binding cassette transporter subunit, accelerated bacterial clearance in INH-treated mice without affecting growth or survival in untreated mice. Conversely, transposon insertions within the rv0096-rv0101 gene cluster attenuated bacterial growth and survival in untreated mice but paradoxically prevented INH-mediated killing of bacteria in treated mice. These contrasting phenotypes were dependent on the interaction of the bacteria with the tissue environment because both mutants responded normally to INH when grown in macrophages ex vivo or in axenic cultures in vitro. Our findings have important implications because persistence-impairing mutations would be missed by conventional genetic screens to identify candidate drug targets. Conversely, persistenceenhancing mutations would be missed by standard diagnostic methods, which are performed on bacteria grown in vitro, to detect drug resistance.chemotherapy | drug tolerance | host environment T uberculosis (TB) has been a treatable disease for more than half a century, yet TB eradication remains a distant and possibly unachievable goal barring the introduction of more effective control strategies (1). A formidable obstacle to successful treatment of TB is the requirement for frequent administration of multiple drugs for 6 mo or longer (2). Unless drug administration is closely supervised, the majority of patients will not adhere to such a protracted therapeutical regimen (2). Consequently, patient nonadherence is responsible for high rates of treatment failure, relapse, and emergent drug resistance (3). To reduce treatment costs and improve patient adherence, there is an urgent need for more effective anti-TB drugs to shorten the treatment time (2, 4).Conventional anti-TB drugs target biosynthetic processes involved in cell growth, including RNA transcription [rifampicin (RIF)], protein translation (streptomycin), and cell wall biogenesis [isoniazid (INH)]. Although these drugs rapidly kill Mycobacterium tuberculosis grown in vitro, they are less active against bacteria grown in vivo in mammalian hosts (4,5). In the mouse model of TB, infection progresses through a brief ac...

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Section: Discussionmentioning

confidence: 99%

Mycobacterium tuberculosis persistence mutants identified by screening in isoniazid-treated mice

Dhar

McKinney

2010

Proc. Natl. Acad. Sci. U.S.A.

113

106

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“…delivered an excellent example of how to target a transcription factor by structure‐based design in order to positively influence the genetic machinery of a bacterium with respect to its susceptibility against a given antibiotic agent 191. They targeted the transcriptional repressor EthR, a member of the TetR family of repressors,193 which blocks the transcription of ethA .…”

Section: Intervention At the Genetic Levelmentioning

confidence: 99%

Targeting Antibiotic Resistance

2016

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Finding strategies against the development of antibiotic resistance is a major global challenge for the life sciences community and for public health. The past decades have seen a dramatic worldwide increase in human‐pathogenic bacteria that are resistant to one or multiple antibiotics. More and more infections caused by resistant microorganisms fail to respond to conventional treatment, and in some cases, even last‐resort antibiotics have lost their power. In addition, industry pipelines for the development of novel antibiotics have run dry over the past decades. A recent world health day by the World Health Organization titled “Combat drug resistance: no action today means no cure tomorrow” triggered an increase in research activity, and several promising strategies have been developed to restore treatment options against infections by resistant bacterial pathogens.

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“…Ces travaux débouchent sur un nombre croissant de publications, démon-trant, si besoin était, leur utilité tant d'un point de vue fondamental que médical. Ainsi, sur les 4 dernières années, une soixantaine de travaux issus de laboratoires français et reposant sur un criblage ont été publiés, pour certains dans des revues à très haut facteur d'impact [28][29][30]. Parallèlement, ces travaux ont fait l'objet d'une vingtaine de brevets.…”

Section: Limites De Ces Techniques De Recherche De La Cibleunclassified