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      Drug Design, Development and Therapy (submit here)

      This international, peer-reviewed Open Access journal by Dove Medical Press focuses on the design and development of drugs, as well as the clinical outcomes, patient safety, and programs targeted at the effective and safe use of medicines. Sign up for email alerts here.

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      Profiling Pretomanid as a Therapeutic Option for TB Infection: Evidence to Date

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          Abstract

          Tuberculosis (TB) is the most deadly infectious disease globally. Although most individuals achieve a cure, a substantial portion develop multi-drug resistant TB which is exceedingly difficult to treat, and the number of effective agents is dwindling. Development of new anti-tubercular medications is imperative to combat existing drug resistance and accelerate global eradication of TB. Pretomanid (PA-824) represents one of the newest drug classes (ie, nitroimidazooxazines) approved in 2019 by the United States Food and Drug Administration as part of a multi-drug regimen (with bedaquiline and linezolid, BPaL) and recommended by the World Health Organization (WHO) to treat extensively-resistant (XR-TB) and multi-drug resistant tuberculosis (MDR-TB). Approval was granted through the FDA’s Limited Population Pathway for Antibacterial and Antifungal Drugs, which accelerates approval for antimicrobial drugs used to treat life-threatening or serious infections in a limited population with unmet need. This review details the pharmacology, efficacy, and safety of this new agent and describes evidence to date for its role in the treatment of drug resistant TB including published, ongoing, and planned studies.

          Most cited references79

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          Genes required for mycobacterial growth defined by high density mutagenesis.

          Christopher Sassetti, Dana Boyd, Eric Rubin (2003)
          Despite over a century of research, tuberculosis remains a leading cause of infectious death worldwide. Faced with increasing rates of drug resistance, the identification of genes that are required for the growth of this organism should provide new targets for the design of antimycobacterial agents. Here, we describe the use of transposon site hybridization (TraSH) to comprehensively identify the genes required by the causative agent, Mycobacterium tuberculosis, for optimal growth. These genes include those that can be assigned to essential pathways as well as many of unknown function. The genes important for the growth of M. tuberculosis are largely conserved in the degenerate genome of the leprosy bacillus, Mycobacterium leprae, indicating that non-essential functions have been selectively lost since this bacterium diverged from other mycobacteria. In contrast, a surprisingly high proportion of these genes lack identifiable orthologues in other bacteria, suggesting that the minimal gene set required for survival varies greatly between organisms with different evolutionary histories.
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            Genetic requirements for mycobacterial survival during infection.

            C M Sassetti, E. J. Rubin (2011)
            Despite the importance of tuberculosis as a public health problem, we know relatively little about the molecular mechanisms used by the causative organism, Mycobacterium tuberculosis, to persist in the host. To define these mechanisms, we have mutated virtually every nonessential gene of M. tuberculosis and determined the effect disrupting each gene on the growth rate of this pathogen during infection. A total of 194 genes that are specifically required for mycobacterial growth in vivo were identified. The behavior of these mutants provides a detailed view of the changing environment that the bacterium encounters as infection proceeds. A surprisingly large fraction of these genes are unique to mycobacteria and closely related species, indicating that many of the strategies used by this unusual group of organisms are fundamentally different from other pathogens
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              Bedaquiline, pretomanid and linezolid for treatment of extensively drug resistant, intolerant or non-responsive multidrug resistant pulmonary tuberculosis

              Francesca Conradie, Andreas Diacon, Nosipho Ngubane … (2020)
              Background Patients with extensively drug resistant tuberculosis (TB) have limited treatment options with historically poor outcomes. We investigated treatment with 3 oral drugs, bedaquiline (B), pretomanid (Pa) and linezolid (L), (B-Pa-L), with TB bactericidal activity and little pre-existing resistance. Methods Nix-TB is an open label single arm study ongoing at three South African sites evaluating the safety and efficacy of B-Pa-L for 26 weeks for extensively drug-resistant TB or treatment intolerant /non-responsive multidrug-resistant TB. We present the efficacy and safety outcomes for all 109 patients enrolled in the trial followed to the predefined primary endpoint, six months after the end of treatment. Results In the intent to treat analysis, 98 patients (90%), (95% CI 82.7-94.9%) had a favourable outcome at 6 months after the end of treatment. Six patients died during the early stages of treatment, one withdrew during treatment, one died during follow-up without evidence of relapse, one relapsed, one relapsed and subsequently died during follow up and one was lost to follow-up. The expected linezolid toxicities of peripheral neuropathy (experienced by 81% of patients) and myelosuppression (48%), while common, were manageable, often requiring reductions of dose and/or interruptions in linezolid. Conclusions These results suggest that B-Pa-L is a viable option for tuberculosis patients with highly resistant forms of TB, provided adequate safety management is available. Trial registration: ClinicalTrials.gov Identifier: NCT02333799 Sponsor: Global Alliance for TB Drug Development (TB Alliance)
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                Author and article information

                Journal
                Journal ID (nlm-ta): Drug Des Devel Ther
                Journal ID (iso-abbrev): Drug Des Devel Ther
                Journal ID (publisher-id): dddt
                Journal ID (pmc): dddt
                Title: Drug Design, Development and Therapy
                Publisher: Dove
                ISSN (Electronic): 1177-8881
                Publication date (Electronic): 28 June 2021
                Publication date Collection: 2021
                Volume: 15
                Pages: 2815-2830
                Affiliations
                [1 ]Division of Adolescent Medicine, Children’s Mercy Kansas City , Kansas City, MO, 64108, USA
                [2 ]Division of Clinical Pharmacology, Toxicology and Therapeutic Innovation, Children’s Mercy Kansas City , Kansas City, MO, 64108, USA
                [3 ]Department of Pediatrics, University of Missouri-Kansas City School of Medicine , Kansas City, MO, 64108, USA
                [4 ]World Health Organization , Geneva, Switzerland
                Author notes
                Correspondence: Susan M Abdel-Rahman Division of Clinical Pharmacology, Toxicology and Therapeutic Innovation, Children’s Mercy Kansas City , 2401 Gillham Road, Kansas City, MO, 64108, USATel +1 816-731-7164 Email srahman@cmh.edu
                Article
                Publisher ID: 281639
                DOI: 10.2147/DDDT.S281639
                PMC ID: 8253981
                PubMed ID: 34234413
                SO-VID: 527a9bb4-b3a9-49f2-83e7-0cd2bcfda25b
                Copyright © © 2021 Stancil et al.
                License:

                This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms ( https://www.dovepress.com/terms.php).

                History
                Date received : 01 April 2021
                Date accepted : 28 May 2021
                Page count
                Figures: 2, Tables: 10, References: 83, Pages: 16
                Categories
                Subject: Review

                ScienceOpen disciplines: Pharmacology & Pharmaceutical medicine
                Keywords: pretomanid,tuberculosis,antimicrobial,multi-drug resistant
                Data availability:
                ScienceOpen disciplines: Pharmacology & Pharmaceutical medicine
                Keywords: pretomanid, tuberculosis, antimicrobial, multi-drug resistant

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