Strategies for potentiation of ethionamide and folate antagonists against<i>Mycobacterium tuberculosis</i>

Wolff, Kerstin; Nguyen, Liem

doi:10.1586/eri.12.87

Cited by 25 publications

(24 citation statements)

References 82 publications

(201 reference statements)

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“…Yet, a parallel study reported that while sulfamethoxazole alone showed measurable activity against various M. tuberculosis isolates, no apparent improvement of trimethoprim activity was observed (70). Interestingly, it has been demonstrated that specific disruptions in the folate interconversion pathway can modulate the susceptibility of M. smegmatis to various trimethoprim-sulfonamide combinations (72), suggesting opportunities for potentiation of antifolate action in mycobacteria (73).…”

Section: Folate Metabolism As a High-value Drug Targetmentioning

confidence: 99%

Mycobacterium tuberculosis Folate Metabolism and the Mechanistic Basis for para -Aminosalicylic Acid Susceptibility and Resistance

Minato

Thiede

Kordus

et al. 2015

Antimicrob Agents Chemother

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b para-Aminosalicylic acid (PAS) entered clinical use in 1946 as the second exclusive drug for the treatment of tuberculosis (TB). While PAS was initially a first-line TB drug, the introduction of more potent antitubercular agents relegated PAS to the secondline tier of agents used for the treatment of drug-resistant Mycobacterium tuberculosis infections. Despite the long history of PAS usage, an understanding of the molecular and biochemical mechanisms governing the susceptibility and resistance of M. tuberculosis to this drug has lagged behind that of most other TB drugs. Herein, we discuss previous studies that demonstrate PAS-mediated disruption of iron acquisition, as well as recent genetic, biochemical, and metabolomic studies that have revealed that PAS is a prodrug that ultimately corrupts one-carbon metabolism through inhibition of the formation of reduced folate species. We also discuss findings from laboratory and clinical isolates that link alterations in folate metabolism to PAS resistance. These advancements in our understanding of the basis of the susceptibility and resistance of M. tuberculosis to PAS will enable the development of novel strategies to revitalize this and other antimicrobial agents for use in the global effort to eradicate TB. Mycobacterium tuberculosis is responsible for approximately 8.6 million new cases of active tuberculosis (TB) infection and 1.3 million deaths annually despite the existence of TB therapy (1). While this therapy has a high success rate in curing drugsusceptible TB infections, it is challenging, in part because it requires a minimum of 6 months of treatment with drugs that are associated with adverse reactions (2, 3). These factors contribute to treatment errors and noncompliance, which have been implicated in the emergence of drug-resistant strains of M. tuberculosis (4, 5). Further, subsequent relapse of the disease can occur and is associated with a high incidence of drug resistance (6). Together, these complications have enabled the emergent spread of multidrug-resistant (MDR) and extensively drug-resistant (XDR) strains of M. tuberculosis that require greater than 2 years of therapy with second-line drugs and threaten the efficacy of existing TB therapy (1, 7). Elucidating the mechanisms that govern the susceptibility and resistance of M. tuberculosis to existing antitubercular agents will facilitate the discovery of new therapeutic approaches to shorten treatment times and counter drug-resistant TB.para-Aminosalicylic acid (PAS) entered clinical use as a bacteriostatic antitubercular agent in 1946 (8). Shortly before the introduction of PAS, the discovery of streptomycin as a therapeutic tool had dramatically improved TB survival rates (9). At that time, it was apparent that the rapid emergence of streptomycin-resistant M. tuberculosis strains posed a threat to this monotherapy strategy for TB infection (9). As PAS was effective against streptomycinresistant strains of M. tuberculosis (10), it was soon recognized that combination therapy could reduce th...

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Section: Folate Metabolism As a High-value Drug Targetmentioning

confidence: 99%

Mycobacterium tuberculosis Folate Metabolism and the Mechanistic Basis for para -Aminosalicylic Acid Susceptibility and Resistance

Minato

Thiede

Kordus

et al. 2015

Antimicrob Agents Chemother

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“…tuberculosis infections13. The search for new therapeutic options for treatment of drug susceptible as well as drug resistant strains has fueled an effort to repurpose existing drugs for TB therapy45.…”

mentioning

confidence: 99%

Targeting intracellular p-aminobenzoic acid production potentiates the anti-tubercular action of antifolates

Thiede

Kordus

Turman

et al. 2016

Sci Rep

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The ability to revitalize and re-purpose existing drugs offers a powerful approach for novel treatment options against Mycobacterium tuberculosis and other infectious agents. Antifolates are an underutilized drug class in tuberculosis (TB) therapy, capable of disrupting the biosynthesis of tetrahydrofolate, an essential cellular cofactor. Based on the observation that exogenously supplied p-aminobenzoic acid (PABA) can antagonize the action of antifolates that interact with dihydropteroate synthase (DHPS), such as sulfonamides and p-aminosalicylic acid (PAS), we hypothesized that bacterial PABA biosynthesis contributes to intrinsic antifolate resistance. Herein, we demonstrate that disruption of PABA biosynthesis potentiates the anti-tubercular action of DHPS inhibitors and PAS by up to 1000 fold. Disruption of PABA biosynthesis is also demonstrated to lead to loss of viability over time. Further, we demonstrate that this strategy restores the wild type level of PAS susceptibility in a previously characterized PAS resistant strain of M. tuberculosis. Finally, we demonstrate selective inhibition of PABA biosynthesis in M. tuberculosis using the small molecule MAC173979. This study reveals that the M. tuberculosis PABA biosynthetic pathway is responsible for intrinsic resistance to various antifolates and this pathway is a chemically vulnerable target whose disruption could potentiate the tuberculocidal activity of an underutilized class of antimicrobial agents.

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“…Two research groups recently reported the identification of ethionamide potentiators that significantly sensitize M. tuberculosis to the drug through the inactivation of a key resistance mechanism [36]. Hopefully, the introduction of effective potentiators would allow ethionamide to be used as a first-line anti-TB agent [36].…”

Section: Key Pointsmentioning

confidence: 99%

Drug-resistant tuberculosis

Pontali

Matteelli

Migliori

2013

Current Opinion in Pulmonary Medicine

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The innovative diagnostic tools recently validated are changing the traditional paradigms of TB diagnosis, for too long based on sputum smear, culture, and drug susceptibility testing. New anti-TB compounds, which can be combined with several 'old' drugs with new indications, are gradually modifying the chances of cure for MDR-TB cases. Although initial evidence appears promising, the market use of new drugs must be accompanied by a serious public health approach aimed at preventing the development of further drug resistance.

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Strategies for potentiation of ethionamide and folate antagonists againstMycobacterium tuberculosis

Cited by 25 publications

References 82 publications

Mycobacterium tuberculosis Folate Metabolism and the Mechanistic Basis for para -Aminosalicylic Acid Susceptibility and Resistance

Mycobacterium tuberculosis Folate Metabolism and the Mechanistic Basis for para -Aminosalicylic Acid Susceptibility and Resistance

Targeting intracellular p-aminobenzoic acid production potentiates the anti-tubercular action of antifolates

Drug-resistant tuberculosis

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