The small-molecule SMARt751 reverses
            <i>Mycobacterium tuberculosis</i>
            resistance to ethionamide in acute and chronic mouse models of tuberculosis

Flipo, Marion; Frita, Rosangela; Bourotte, Marilyne; Martínez-Martínez, María Santos; Böesche, Markus; Boyle, Gary W; Derimanov, Geo; Drewes, Gerard; Gamallo, Pablo; Ghidelli-Disse, Sonja; Gresham, Stephanie; Jiménez, Elena; Mercado, Jaime de; Pérez-Herrán, Esther; Francisco, Esther Porras-De; Rullás, Joaquín; Casado, Patricia; Leroux, Florence; Piveteau, Catherine; Kiass, Mehdi; Mathys, Vanessa; Soetaert, Karine; Mégalizzi, Veronique; Tanina, Abdalkarim; Wintjens, René; Antoine, Rudy; Brodin, Priscille; Delorme, Vincent; Moune, Martin; Djaout, Kamel; Slupek, Stéphanie; Kemmer, Christian; Gitzinger, Marc; Ballell, Lluís; Mendoza-Losana, Alfonso; Lociuro, Sergio; Deprez, Benoı̂t; Barros, David; Remuiñán, Modesto J.; Willand, Nicolas; Baulard, Alain R.

doi:10.1126/scitranslmed.aaz6280

Cited by 17 publications

(13 citation statements)

References 51 publications

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“…Recently, Willand, Baulard, et al discovered a small molecule SMARt751 that potentiated the efficacy of ethionamide (ETH) against a panel of resistant M. tuberculosis both in vitro and in vivo . Elegant mode of action studies demonstrated that SMARt751 promoted the production of MymA via inhibition of a cryptic negative transcriptional regulator . To date, these systems have received only limited attention.…”

Section: Discussionmentioning

confidence: 99%

Chemical Basis of Combination Therapy to Combat Antibiotic Resistance

Pethe

Chan‐Park

2023

JACS Au

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The antimicrobial resistance crisis is a global health issue requiring discovery and development of novel therapeutics. However, conventional screening of natural products or synthetic chemical libraries is uncertain. Combination therapy using approved antibiotics with inhibitors targeting innate resistance mechanisms provides an alternative strategy to develop potent therapeutics. This review discusses the chemical structures of effective β-lactamase inhibitors, outer membrane permeabilizers, and efflux pump inhibitors that act as adjuvant molecules of classical antibiotics. Rational design of the chemical structures of adjuvants will provide methods to impart or restore efficacy to classical antibiotics for inherently antibiotic-resistant bacteria. As many bacteria have multiple resistance pathways, adjuvant molecules simultaneously targeting multiple pathways are promising approaches to combat multidrug-resistant bacterial infections.

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Section: Discussionmentioning

confidence: 99%

Chemical Basis of Combination Therapy to Combat Antibiotic Resistance

Pethe

Chan‐Park

2023

JACS Au

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“…In contrast, INH is activated by the peroxidase KatG. Both enzymes form a stable covalent adduct with nicotinamide adenine dinucleotide (NAD) 46 that inhibits InhA, which is involved in mycolic acid biosynthesis. 37,45,47,48 As DA-CB may also inhibit mycolic acid biosynthesis, we investigated the cellular processes that DA-CB alters by employing a multi-omics approach to characterize the metabolome, proteome, and lipidome of Msm.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

“…In contrast, INH is activated by the peroxidase KatG. Both enzymes form a stable covalent adduct with nicotinamide adenine dinucleotide (NAD) that inhibits InhA, which is involved in mycolic acid biosynthesis. ,,, …”

Section: Resultsmentioning

confidence: 99%

Multi-omics Investigation into the Mechanism of Action of an Anti-tubercular Fatty Acid Analogue

et al. 2022

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The mechanism of action (MoA) of a clickable fatty acid analogue 8-(2-cyclobuten-1-yl)octanoic acid (DA-CB) has been investigated for the first time. Proteomics, metabolomics, and lipidomics were combined with a network analysis to investigate the MoA of DA-CB against Mycobacterium smegmatis (Msm). The metabolomics results showed that DA-CB has a general MoA related to that of ethionamide (ETH), a mycolic acid inhibitor that targets enoyl-ACP reductase (InhA), but DA-CB likely inhibits a step downstream from InhA. Our combined multi-omics approach showed that DA-CB appears to disrupt the pathway leading to the biosynthesis of mycolic acids, an essential mycobacterial fatty acid for both Msm and Mycobacterium tuberculosis (Mtb). DA-CB decreased keto-meromycolic acid biosynthesis. This intermediate is essential in the formation of mature mycolic acid, which is a key component of the mycobacterial cell wall in a process that is catalyzed by the essential polyketide synthase Pks13 and the associated ligase FadD32. The multi-omics analysis revealed further collateral alterations in bacterial metabolism, including the overproduction of shorter carbon chain hydroxy fatty acids and branched chain fatty acids, alterations in pyrimidine metabolism, and a predominate downregulation of proteins involved in fatty acid biosynthesis. Overall, the results with DA-CB suggest the exploration of this and related compounds as a new class of tuberculosis (TB) therapeutics. Furthermore, the clickable nature of DA-CB may be leveraged to trace the cellular fate of the modified fatty acid or any derived metabolite or biosynthetic intermediate.

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“…The old antibiotic ETH, which was used for a long time to treat drug-resistant TB [ 1 ], is benefiting from a renewal since the development of new compounds boosting its activity in vivo [ 24 , 25 ] are currently being assessed in a Phase 1 trial (ClinicalTrials.gov n° NCT04654143).…”

Section: Discussionmentioning

confidence: 99%

How a PCR Sequencing Strategy Can Bring New Data to Improve the Diagnosis of Ethionamide Resistance

et al. 2022

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Ethionamide (ETH) is a second-line antituberculosis drug. ETH resistance (ETH-R) is mainly related to the mutations of the monooxygenase-activating ETH (EthA), the ETH target (InhA), and the inhA promoter. Nonetheless, diagnosing ETH-R is still challenging. We assessed the strategy used for detecting ETH-R at the French National Reference Center for Mycobacteria in 497 MDR-TB isolates received from 2008 to 2016. The genotypic ETH’s resistance detection was performed by sequencing ethA, ethR, the ethA-ethR intergenic region, and the inhA promoter in the 497 multidrug-resistant isolates, whereas the phenotypic ETH susceptibility testing (PST) was performed using the reference proportion method. Mutations were found in up to 76% of the 387 resistant isolates and in up to 28% of the 110 susceptible isolates. Our results do not support the role of ethR mutations in ETH resistance. Altogether, the positive predictive value of our genotypic strategy to diagnose ETH-R was improved when only considering the variants included in the WHO catalogue and in other databases, such as TB-Profiler. Therefore, our work will help to update the list of mutations that could be graded as being associated with resistance to improve ETH-R diagnosis.

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The small-molecule SMARt751 reverses Mycobacterium tuberculosis resistance to ethionamide in acute and chronic mouse models of tuberculosis

Cited by 17 publications

References 51 publications

Chemical Basis of Combination Therapy to Combat Antibiotic Resistance

Chemical Basis of Combination Therapy to Combat Antibiotic Resistance

Multi-omics Investigation into the Mechanism of Action of an Anti-tubercular Fatty Acid Analogue

How a PCR Sequencing Strategy Can Bring New Data to Improve the Diagnosis of Ethionamide Resistance

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