Targeting protein biotinylation enhances tuberculosis chemotherapy

Tiwari, Divya; Park, Sae Woong; Essawy, Maram M.; Dawadi, Surendra; Mason, Alan; Nandakumar, Madhumitha; Zimmerman, Matthew; Mina, Marizel; Ho, Hsin Pin; Engelhart, Curtis A.; Ioerger, Thomas R.; Sacchettini, James C.; Rhee, Kyu Y.; Ehrt, Sabine; Aldrich, Courtney C.; Dartois, Véronique; Schnappinger, Dirk

doi:10.1126/scitranslmed.aal1803

Cited by 24 publications

(48 citation statements)

References 39 publications

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“…In M. tuberculosis , biotin is a cofactor required for acyl-CoA-carboxylase (ACC) enzymes participating in key metabolic processes in lipid biosynthesis (Takayama et al, 2005 ; Gago et al, 2011 ; Salaemae et al, 2011 ; Woong Park et al, 2011 ). Biotin biosynthesis and protein biotinylation process have been targeted for novel drug development (Duckworth et al, 2011 ; Shi et al, 2013 ; Tiwari et al, 2018 ). On the basis of our in vitro findings, targeting biotin synthesis may promote accumulation of antimycobacterial drugs by disrupting cell envelope integrity, which could revitalize drug therapies that are unable to overcome the relatively impermeable cell envelope of M. tuberculosis at clinically relevant dosages.…”

Section: Discussionmentioning

confidence: 99%

“…On the basis of our in vitro findings, targeting biotin synthesis may promote accumulation of antimycobacterial drugs by disrupting cell envelope integrity, which could revitalize drug therapies that are unable to overcome the relatively impermeable cell envelope of M. tuberculosis at clinically relevant dosages. Indeed, it was recently reported that disruption of protein biotinylation potentiates rifampicin activity against M. tuberculosis (Tiwari et al, 2018 ). It was previously reported that biotin has a vital role in methionine-mediated, PAS antagonism, such that supplementation with exogenous biotin was required to observe antagonism by methionine (Hedgecock, 1956 ).…”

Section: Discussionmentioning

confidence: 99%

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Methionine Antagonizes para-Aminosalicylic Acid Activity via Affecting Folate Precursor Biosynthesis in Mycobacterium tuberculosis

Howe

Kordus

Cole

et al. 2018

Front. Cell. Infect. Microbiol.

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para-Aminosalicylic acid (PAS) is a second-line anti-tubercular drug that is used for the treatment of drug-resistant tuberculosis (TB). PAS efficacy in the treatment of TB is limited by its lower potency against Mycobacterium tuberculosis relative to many other drugs in the TB treatment arsenal. It is known that intrinsic metabolites, such as, para-aminobenzoic acid (PABA) and methionine, antagonize PAS and structurally related anti-folate drugs. While the basis for PABA-mediated antagonism of anti-folates is understood, the mechanism for methionine-based antagonism remains undefined. In the present study, we used both targeted and untargeted approaches to identify factors associated with methionine-mediated antagonism of PAS activity. We found that synthesis of folate precursors as well as a putative amino acid transporter, designated MetM, play crucial roles in this process. Disruption of metM by transposon insertion resulted in a ≥30-fold decrease in uptake of methionine in M. bovis BCG, indicating that metM is the major facilitator of methionine transport. We also discovered that intracellular biotin confers intrinsic PAS resistance in a methionine-independent manner. Collectively, our results demonstrate that methionine-mediated antagonism of anti-folate drugs occurs through sustained production of folate precursors.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Methionine Antagonizes para-Aminosalicylic Acid Activity via Affecting Folate Precursor Biosynthesis in Mycobacterium tuberculosis

Howe

Kordus

Cole

et al. 2018

Front. Cell. Infect. Microbiol.

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“…Inhibitor of BirA can also enhance the potency of current TB drugs. This was suggested in a recent study showing the increased potency of INH and RIF when combined with BirA inhibitor Bio-AMS (5 0 -[N-(d-biotinoyl) sulfamoyl] amino-5 0 -deoxyadenosine) [153]. Since Bio-AMS is selective for Mtb and its drug-resistant strains, it does not affect other commensal bacteria as well as human cell lines [152].…”

Section: Biotinylationmentioning

confidence: 98%

Role of post‐translational modifications in the acquisition of drug resistance in Mycobacterium tuberculosis

et al. 2020

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Tuberculosis (TB) is one of the primary causes of deaths due to infectious diseases. The current TB regimen is long and complex, failing of which leads to relapse and/or the emergence of drug resistance. There is a critical need to understand the mechanisms of resistance development. With increasing drug pressure, Mycobacterium tuberculosis (Mtb) activates various pathways to counter drug-related toxicity. Signaling modules steer the evolution of Mtb to a variant that can survive, persist, adapt, and emerge as a form that is resistant to one or more drugs. Recent studies reveal that about 1/3rd of the annotated Mtb proteome is modified post-translationally, with a large number of these proteins being essential for mycobacterial survival. Post-translational modifications (PTMs) such as phosphorylation, acetylation, and pupylation play a salient role in mycobacterial virulence, pathogenesis, and metabolism. The role of many other PTMs is still emerging. Understanding the signaling pathways and PTMs may assist clinical strategies and drug development for Mtb. In this review, we explore the contribution of PTMs to mycobacterial physiology, describe the related cellular processes, and discuss how these processes are linked to drug resistance. A significant number of drug targets, InhA, RpoB, EmbR, and KatG, are modified at multiple residues via PTMs. A better understanding of drug-resistance regulons and associated PTMs will aid in developing effective drugs against TB.

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“…The structurally distinct mycobacterial lipids, derived from malonyl coenzyme A (CoA) are assembled with acyl-CoA carboxylases (ACC) subunits, AccA1 to AccA3, AccD1 to AccD6, AccE5. Moreover, ACC is an essential factor for fatty acids, mycolates and lipid synthesis of Mtb along with biotin (vitamin H or vitamin B7), as the cofactor in the posttranslational process [59][60][61][62]. Thus, de novo biotin biosynthesis or biotin-ACC ligation inhibition is a new target for Mtb inhibition.…”

Section: Resistance Mechanism Of Drug Targeting Cell Wall Mycolic Acmentioning

confidence: 99%

Molecular mechanisms of underlying genetic factors and associated mutations for drug resistance in Mycobacterium tuberculosis

Swain

Sharma

Hussain

2020

Emerging Microbes & Infections

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Nowadays, drug-resistant tuberculosis (DR-TB) and co-infected tuberculosis (CI-TB) strains are the leading cause for the enhancement of long-term morbidity and unpredicted mortality rates from this ghoulish acid fast-bacterium infection, globally. Unfortunately, the lack of/ample lethargic towards the development of compelling anti-TB regimens with a large-scale prevalence rate is a great challenge towards control of the pandemic situation. Indeed, the recent improvement in genomic studies for early diagnosis and understanding the mechanisms of drug resistance, as well as the identification of newer drug targets is quite remarkable and promising. Mainly, identification of such genetic factors, chromosomal mutations and associated pathways gives new ray of hope in current anti-TB drug discovery. This focused review provides molecular insights into the updated drug resistance mechanisms with encoded bacilli genetic factors as a novel target and potential source of development with screened-out newer anti-TB agents towards the control of MDR-TB soon.

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Targeting protein biotinylation enhances tuberculosis chemotherapy

Cited by 24 publications

References 39 publications

Methionine Antagonizes para-Aminosalicylic Acid Activity via Affecting Folate Precursor Biosynthesis in Mycobacterium tuberculosis

Methionine Antagonizes para-Aminosalicylic Acid Activity via Affecting Folate Precursor Biosynthesis in Mycobacterium tuberculosis

Role of post‐translational modifications in the acquisition of drug resistance in Mycobacterium tuberculosis

Molecular mechanisms of underlying genetic factors and associated mutations for drug resistance in Mycobacterium tuberculosis

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