SQ109 and PNU-100480 interact to kill Mycobacterium tuberculosis in vitro

Reddy, Venkata M.; Dubuisson, Tia; Einck, Leo; Wallis, Robert S.; Jakubiec, Wesley; Ladukto, Lynn; Campbell, Sheldon; Nacy, Carol A.

doi:10.1093/jac/dkr589

Cited by 41 publications

(19 citation statements)

References 10 publications

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“…Studies into the biological activity of A-500359 A, the major congener isolated from S. griseus SANK 60196, and several semisynthetic analogues have revealed a potential utility of these natural products as anti-tuberculosis antibiotics (9,10). For example, SQ641 and SQ922, two leads under preclinical development by Sequella (Rockville, MD), have been shown to have several clinically desirable attributes, including in vitro activity against multiple-drug-resistant strains of Mycobacterium tuberculosis (the primary causative agent of tuberculosis); high efficacy in a murine model of tuberculosis; rapid kill time in vitro and in vivo; and no toxicity to mice (11)(12)(13)(14)(15)(16)(17). Given the widespread documentation of extensively drug-resistant M. tuberculosis and the recent reality of totally drug-resistant M. tuberculosis (18), the development of drugs with novel targets, such as the capuramycin-type antibiotics, makes them attractive leads for tuberculosis chemotherapy (19,20).…”

Section: Capuramycin-type Antibiotics Include A-500359s Frommentioning

confidence: 99%

The Biosynthesis of Capuramycin-type Antibiotics

Cai

Goswami

Yang

et al. 2015

Journal of Biological Chemistry

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Background: Several nucleoside antibiotics contain a uridine-5Ј-carboxamide core of unclear origin. Results: The A-102395 biosynthetic gene cluster was cloned, a genetic system was developed, and three enzymes were characterized in vivo and in vitro. Conclusion: Uridine-5Ј-carboxamide originates from UMP and L-Thr by sequential reactions catalyzed by a dioxygenase and transaldolase. Significance: The results provide the first opportunity to methodically interrogate the biosynthesis of these unusual antibiotics.

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Section: Capuramycin-type Antibiotics Include A-500359s Frommentioning

confidence: 99%

The Biosynthesis of Capuramycin-type Antibiotics

Cai

Goswami

Yang

et al. 2015

Journal of Biological Chemistry

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“…The rate of killing by isoniazid in M. tuberculosis H37Rv and the MmrKO mutant was determined as previously described (28). Isoniazid was diluted in 10 ml of Middlebrook 7H9 supplemented with 10% ADC to give 2ϫ, 4ϫ, and 8ϫ MIC.…”

Section: Drug Susceptibility Assays (I) Determination Of Micsmentioning

confidence: 99%

Role of the Mmr Efflux Pump in Drug Resistance in Mycobacterium tuberculosis

Rodrigues

Villellas

Bailo

et al. 2013

Antimicrob Agents Chemother

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Efflux pumps are membrane proteins capable of actively transporting a broad range of substrates from the cytoplasm to the exterior of the cell. Increased efflux activity in response to drug treatment may be the first step in the development of bacterial drug resistance. Previous studies showed that the efflux pump Mmr was significantly overexpressed in strains exposed to isoniazid. In the work to be described, we constructed mutants lacking or overexpressing Mmr in order to clarify the role of this efflux pump in the development of resistance to isoniazid and other drugs in M. tuberculosis. The mmr knockout mutant showed an increased susceptibility to ethidium bromide, tetraphenylphosphonium, and cetyltrimethylammonium bromide (CTAB). Overexpression of mmr caused a decreased susceptibility to ethidium bromide, acriflavine, and safranin O that was obliterated in the presence of the efflux inhibitors verapamil and carbonyl cyanide m-chlorophenylhydrazone. Isoniazid susceptibility was not affected by the absence or overexpression of mmr. The fluorometric method allowed the detection of a decreased efflux of ethidium bromide in the knockout mutant, whereas the overexpressed strain showed increased efflux of this dye. This increased efflux activity was inhibited in the presence of efflux inhibitors. Under our experimental conditions, we have found that efflux pump Mmr is mainly involved in the susceptibility to quaternary compounds such as ethidium bromide and disinfectants such as CTAB. The contribution of this efflux pump to isoniazid resistance in Mycobacterium tuberculosis still needs to be further elucidated.

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“…The drug has shown favorable in vitro effects when used in combination with bedaquiline and sutezolid. 47,48 In the first study of SQ109 in patients with pulmonary TB, SQ109 was administered at variable doses up to 300 mg daily, with or without coadministration of rifampicin for 14 days. 49 SQ109 was found to be safe and generally well tolerated at the doses administered, with mild-to-moderate gastrointestinal complaints being the most frequent adverse event reported.…”

Section: Pretomanidmentioning

confidence: 99%

Novel Treatments for Drug-Resistant Tuberculosis

Clain

Escalante

2016

Clinical Medicine Insights: Therapeutics

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Drug resistance has emerged as a major obstacle to global control of tuberculosis (TB). Treatment with currently available medications requires prolonged courses of numerous drugs, many of which are associated with significant adverse effects. New drugs are urgently needed to meet the challenge posed by drug-resistant TB, in order to relieve the burden that drug resistance has placed on individual patients and health systems. Fortunately, many new drugs have been developed for the treatment of drug-resistant TB in recent years. The new antimycobacterial agents are derived from various medication classes, work by means of an assortment of mechanisms of action, and are at differing phases of development. This review provides a survey of the most promising new agents, in order to promote familiarity with these emerging drugs and compounds.

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SQ109 and PNU-100480 interact to kill Mycobacterium tuberculosis in vitro

Abstract: SQ109 and PNU combinations were additive and improved the rate of MTB killing over individual drugs. These data suggest that the drugs may work together cooperatively to eliminate MTB in vivo.

Cited by 41 publications

References 10 publications

The Biosynthesis of Capuramycin-type Antibiotics

The Biosynthesis of Capuramycin-type Antibiotics

Role of the Mmr Efflux Pump in Drug Resistance in Mycobacterium tuberculosis

Novel Treatments for Drug-Resistant Tuberculosis

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