Bactericidal and Sterilizing Activity of a Novel Regimen with Bedaquiline, Pretomanid, Moxifloxacin, and Pyrazinamide in a Murine Model of Tuberculosis

Li, Si Yang; Tasneen, Rokeya; Tyagi, Sandeep; Soni, Heena; Converse, Paul J.; Mdluli, Khisimuzi; Nuermberger, Eric L.

doi:10.1128/aac.00913-17

Cited by 85 publications

(108 citation statements)

References 17 publications

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“…As representatives of one of only two new drug classes approved for use against TB in roughly 50 years, delamanid and pretomanid are important and promising new drugs (3,4,6,7,39). The former received accelerated approval from the EMA for treatment of MDR-TB and is now used tuberculosis complex (16,18,(21)(22)(23)40).…”

Section: Discussionmentioning

confidence: 99%

“…To date, emergence of resistance has not been described during use of pretomanid in clinical trials, but such use has been restricted to relatively short treatment durations and/or use of highly active companion drugs. Pretomanid resistance has emerged during combination therapy in mouse models (3,46 (22), clearly challenges the development and interpretation of rapid molecular susceptibility tests, especially considering that polymorphisms in nitroimidazole resistance genes that represent phylogenetic markers but do not confer pretomanid resistance are well-described (47,48). A similar situation exists for pncA mutations and pyrazinamide (PZA) resistance, where an efficient, yet comprehensive method based on saturating mutagenesis for distinguishing single nucleotide polymorphisms conferring resistance was recently described (49).…”

Section: Discussionmentioning

confidence: 99%

“…The emergence and spread of multidrug-resistant (MDR) and extensively drug-resistant (XDR) M. tuberculosis makes the eradication effort much more difficult because treatment requires administration of more toxic and less effective second-and third-line drugs for up to 2 years (1,2). Delamanid and pretomanid are promising new bicyclic 4-nitroimidazole drugs that have shown potential in preclinical and clinical studies to shorten and simplify the treatment of TB, including drug-resistant forms (3)(4)(5)(6)(7)(8)(9). Delamanid received conditional approval by the European Medicines Agency (EMA) to treat MDR-TB in 2014 (10) and pretomanid is currently being evaluated in Phase 2/3 clinical trials (ClinicalTrials.gov Identifiers: NCT03338621, NCT02589782, NCT02333799, NCT03086486).…”

Section: Introductionmentioning

confidence: 99%

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Mutations in Rv2983 as a novel determinant of resistance to nitroimidazole drugs in Mycobacterium tuberculosis

Rifat

Ioerger

et al. 2018

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SIGNIFICANCENitroimidazole pro-drugs represent a promising new class of anti-tuberculosis drugs. Reliable methods to assure nitroimidazole susceptibility are critical to assure their optimal use. Yet, the spectrum of nitroimidazole resistance mutations remains incompletely characterized. Using 161 pretomanid-resistant Mycobacterium tuberculosis isolates selected in pretomanid-treated mice, we discovered a novel resistance determinant, Rv2983, required for cofactor F420 biosynthesis and characterized the remarkable diversity of mutations in this and 5 other genes involved in nitroimidazole activation. We show that F420H2-deficient nitroimidazole-resistant mutants are hypersusceptible to the selective decontaminant malachite green used in solid media to isolate mycobacteria and may evade detection on such media. These results have important implications for development and clinical use of genotypic and phenotypic methods for nitroimidazole susceptibility testing. ABSTRACTDelamanid represents one of two novel antimicrobial classes approved to treat tuberculosis in over 40 years. Pretomanid is another promising nitroimidazole pro-drug in clinical development.Characterization of the full spectrum of mutations conferring resistance to nitroimidazoles and their related phenotypes in Mycobacterium tuberculosis will inform development of suitable genotypic and phenotypic drug susceptibility tests. Here, we used a range of pretomanid doses to select pretomanid-resistant mutants in two pathologically distinct murine TB models. The frequency of spontaneous pretomanid resistance mutations was approximately 10 -5 CFU.Pretomanid demonstrated dose-dependent bactericidal activity and selective amplification of resistant mutants. Whole genome sequencing of 161 resistant isolates from 47 mice revealed 99 unique mutations, 90% of which were found in 1 of 5 genes previously associated with nitroimidazole activation and resistance. The remaining 10% harbored isolated mutations in Rv2983. Complementing an Rv2983 mutant with a wild-type copy of Rv2983 restored wild-type susceptibility to pretomanid and delamanid, confirming that loss of Rv2983 function causes nitroimidazole resistance. By quantifying F420 and its precursor Fo in Mycobacterium smegmatis overexpressing Rv2983 and an M. tuberculosis Rv2983 mutant, we provide evidence that Rv2983 is necessary for F420 biosynthesis and nitroimidazole activation, perhaps as the guanylyltransferase CofC. F420H2-deficient mutants displayed hypersusceptibility to malachite green (MG), a selective decontaminant present in solid media used to isolate and propagate mycobacteria from clinical samples. The wide diversity of mutations causing high-level pretomanid resistance and MG hypersusceptibility of most mutants poses significant challenges to clinical detection of nitroimidazole resistance using either genotypic or phenotypic methods.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Mutations in Rv2983 as a novel determinant of resistance to nitroimidazole drugs in Mycobacterium tuberculosis

Rifat

Ioerger

et al. 2018

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“…However, the trial was temporarily put on hold owing to concerns about hepatotoxicity before the sponsor discontinued enrolment in favour of a new phase 2 trial SimpliciTB (NCT03338621) that will evaluate a more promising 4-month 4-drug regimen that combines bedaquiline with pretomanid, moxifloxacin and pyrazinamide. This regimen is much more potent in mice, 55 and was associated with near-100% sputum culture conversion in MDR-TB patients at 2 months of treatment using the stringent MGIT-960 liquid culture system (unpublished data of NC-005 trial presented in the 47th Union World Conference on Lung Health in 2016).…”

Section: Drug-susceptible Tb: Alternative Regimens That May Help Facimentioning

confidence: 99%

New drugs and regimens for tuberculosis

et al. 2018

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Since standardized rifampin-based first-line regimens and fluoroquinolone-based second-line regimens were used to treat tuberculosis (TB), unfortunately without timely modification according to the drug resistance profile, TB and drug-resistant disease are still important public health threats worldwide. Although the last decade has witnessed advances in rapid diagnostic tools and use of repurposed and novel drugs for better managing drug-resistant TB, we need an appropriate TB control strategy and a well-functioning health infrastructure to ensure optimal operational use of rapid tests, judicious use of effective treatment regimens that can be rapidly tailored according to the drug resistance profile and timely management of risk factors and co-morbidities that promote infection and its progression to disease. We searched the published literature to discuss (i) standardized versus individualized therapies, including the choice between a single one-size-fit-all regimen versus different options with different key drugs determined mainly by rapid drug susceptibility testing, (ii) alternative regimens for managing drug-susceptible TB, (iii) evidence for using the World Health Organization (WHO) longer and shorter regimens for multidrug-resistant TB and (iv) evidence for using repurposed and novel drugs. We hope an easily applicable combination of biomarkers that accurately predict individual treatment outcome will soon be available to ultimately guide individualized therapy.

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“…The combination of bedaquiline (BDQ) + pretomanid (PMD) + moxifloxacin (MXF) + PZA (regimen abbreviated as BPaMZ) had superior bactericidal and sterilizing activity compared to RIF+INH+PZA in a murine model of TB, shortening the duration of treatment required to prevent relapse by 2.5-3.5 months (4). In the subsequent phase 2 NC-005 trial (NCT02193776), PZA-susceptible MDR-TB patients receiving the BPaMZ regimen had significantly faster sputum culture conversion than drug-susceptible TB patients receiving RIF+INH+PZA+EMB (5), suggesting that the results in mice may translate well to the clinic.…”

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Contribution of pretomanid to novel regimens containing bedaquiline with either linezolid or moxifloxacin and pyrazinamide in murine models of tuberculosis

Almeida

et al. 2019

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Novel regimens combining bedaquiline and pretomanid with either linezolid (BPaL regimen) or moxifloxacin and pyrazinamide (BPaMZ regimen) shorten the treatment duration needed to cure TB in BALB/c mice compared to the first-line regimen and have yielded promising results in initial clinical trials. However, the independent contribution of the investigational new drug pretomanid to the efficacy of BPaMZ has not been examined and its contribution to BPaL has been examined only over the first 2 months of treatment. In the present study, the addition of pretomanid to BL increased bactericidal activity, prevented emergence of bedaquiline resistance, and shortened the duration needed to prevent relapse with drug-susceptible isolates by at least 2 months in BALB/c mice. Addition of pretomanid to BMZ resulted in a 1 log10 greater CFU reduction after 1 month of treatment and/or reduced the number of mice relapsing in each of 2 experiments in BALB/c mice and in immunocompromised nude mice. Bedaquiline-resistant isolates were found at relapse in only one BMZ-treated nude mouse. Treatment of infection with a pyrazinamide-resistant mutant in BALB/c mice with BPaMZ prevented selection of bedaquiline-resistant mutants and reduced the proportion of mice relapsing compared to BMZ alone. Among severely ill C3HeB/FeJ mice with caseous pneumonia and cavitation, BPaMZ increased median survival (≥60 vs. 21 days) and reduced median lung CFU by 2.4 log10 at 1 month compared to BMZ. In conclusion, in 3 different mouse models, pretomanid contributed significantly to the efficacy of the BPaMZ and BPaL regimens, including restricting the selection of bedaquiline-resistant mutants.

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Bactericidal and Sterilizing Activity of a Novel Regimen with Bedaquiline, Pretomanid, Moxifloxacin, and Pyrazinamide in a Murine Model of Tuberculosis

Cited by 85 publications

References 17 publications

Mutations in Rv2983 as a novel determinant of resistance to nitroimidazole drugs in Mycobacterium tuberculosis

Mutations in Rv2983 as a novel determinant of resistance to nitroimidazole drugs in Mycobacterium tuberculosis

New drugs and regimens for tuberculosis

Contribution of pretomanid to novel regimens containing bedaquiline with either linezolid or moxifloxacin and pyrazinamide in murine models of tuberculosis

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