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Functionalized Dioxonaphthoimidazoliums: A Redox Cycling Chemotype with Potent Bactericidal Activities against Mycobacterium tuberculosis.

ABSTRACT: Disruption of redox homeostasis in mycobacteria causes irreversible stress induction and cell death. Here, we report the dioxonaphthoimidazolium scaffold as a novel redox cycling antituberculosis chemotype with potent bactericidal activity against growing and nutrient-starved phenotypically drug-resistant nongrowing bacteria. Maximal potency was dependent on the activation of the redox cycling quinone by the positively charged scaffold and accessibility to the mycobacterial cell membrane as directed by the lipophilicity and conformational characteristics of the N-substituted side chains. Evidence from microbiological, biochemical, and genetic investigations implicates a redox-driven mode of action that is reliant on the reduction of the quinone by type II NADH dehydrogenase (NDH2) for the generation of bactericidal levels of the reactive oxygen species (ROS). The bactericidal profile of a potent water-soluble analogue 32 revealed good activity against nutrient-starved organisms in the Loebel model of dormancy, low spontaneous resistance mutation frequency, and synergy with isoniazid in the checkerboard assay.

SUBMITTER: Fridianto KT

PROVIDER: S-EPMC8595825 | biostudies-literature | 2021 Nov

REPOSITORIES: biostudies-literature

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Functionalized Dioxonaphthoimidazoliums: A Redox Cycling Chemotype with Potent Bactericidal Activities against <i>Mycobacterium tuberculosis</i>.

Fridianto Kevin T KT Li Ming M Hards Kiel K Negatu Dereje A DA Cook Gregory M GM Dick Thomas T Lam Yulin Y Go Mei-Lin ML

Journal of medicinal chemistry 20211027 21

Disruption of redox homeostasis in mycobacteria causes irreversible stress induction and cell death. Here, we report the dioxonaphthoimidazolium scaffold as a novel redox cycling antituberculosis chemotype with potent bactericidal activity against growing and nutrient-starved phenotypically drug-resistant nongrowing bacteria. Maximal potency was dependent on the activation of the redox cycling quinone by the positively charged scaffold and accessibility to the mycobacterial cell membrane as dire ...[more]

PMID: 34706190

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Project description:Multidrug-resistant tuberculosis (MDR-TB) is often associated with poor clinical outcomes. In this study, we evaluated the potential of nosiheptide (NOS) as a new drug candidate for treating Mycobacterium tuberculosis infections, including MDR-TB. The antimicrobial susceptibility testing was performed to determine the MICs of NOS against 18 reference strains of slowly growing mycobacteria (SGM) and 128 clinical isolates of M. tuberculosis. The postantibiotic effects (PAE) and interaction with other antituberculosis drugs of NOS were also evaluated using M. tuberculosis H37Rv. Fifteen out of the 18 tested reference strains of SGM had MICs far below 1 μg/mL. From the 128 M. tuberculosis clinical isolates, the MIC50 and MIC90 were 0.25 μg/mL and 1 μg/mL, respectively; the tentative epidemiological cutoff (ECOFF) was defined at 1 μg/mL. Furthermore, a Lys89Thr mutation was found in one M. tuberculosis isolate with a MIC of NOS >8 μg/mL. After 24 h of incubation, NOS at 1 μg/mL inhibited 25.79 ± 1.22% of intracellular bacterial growth, which was comparable with the inhibitory rate of 25.71 ± 3.67% achieved by rifampin at 2 μg/mL. Compared to rifampicin and isoniazid (INH), NOS had a much longer PAE, i.e., a value of about 16 days. In addition, a partial synergy between NOS and INH was observed. NOS has potent inhibitory activities against M. tuberculosis in vitro as well as in macrophages. Furthermore, the long PAE and partial synergistic effect with INH, in addition to the added safety of long-term use as a feed additive in husbandry, provide support for NOS being a promising drug candidate for tuberculosis treatment. IMPORTANCE This study is aimed at chemotherapy for MDR-TB, mainly to explore the anti-TB activity of the existing chemotherapeutic reagent. We found that NOS has potent inhibitory activities against M. tuberculosis in vitro regardless of the drug-resistant profile. Furthermore, NOS also showed the long PAE and partial synergistic effect with INH and is nontoxic, providing support for its promise as a drug candidate for drug-resistant tuberculosis treatment.

Project description:Ethnopharmacological relevanceEmergence of drug-resistant and multidrug-resistant Mycobacterium tuberculosis (Mtb) strains is a major barrier to tuberculosis (TB) eradication, as it leads to longer treatment regimens and in many cases treatment failure. Thus, there is an urgent need to explore new TB drugs and combinations, in order to shorten TB treatment and improve outcomes. Here, we evaluated the potential of two Asian and African traditional medicinal plants, Artemisia annua, a natural source of artemisinin (AN), and Artemisia afra, as sources of novel antitubercular agents.Aim of the studyOur goal was to measure the activity of A. annua and A. afra extracts against Mtb as potential natural and inexpensive therapies for TB treatment, or as sources of compounds that could be further developed into effective treatments.Materials and methodsThe minimum inhibitory concentrations (MICs) of A. annua and A. afra dichloromethane extracts were determined, and concentrations above the MICs were used to evaluate their ability to kill Mtb and Mycobacterium abscessus in vitro.ResultsPrevious studies showed that A. annua and A. afra inhibit Mtb growth. Here, we show for the first time that Artemisia extracts have a strong bactericidal activity against Mtb. The killing effect of A. annua was much stronger than equivalent concentrations of pure AN, suggesting that A. annua extracts kill Mtb through a combination of AN and additional compounds. A. afra, which produces very little AN, displayed bactericidal activity against Mtb that was substantial but weaker than that of A. annua. In addition, we measured the activity of Artemisia extracts against Mycobacterium abscessus. Interestingly, we observed that while A. annua is not bactericidal, it inhibits growth of M. abscessus, highlighting the potential of this plant in combinatory therapies to treat M. abscessus infections.ConclusionOur results indicate that Artemisia extracts have an enormous potential for treatment of TB and M. abscessus infections, and that these plants contain bactericidal compounds in addition to AN. Combination of extracts with existing antibiotics may not only improve treatment outcomes but also reduce the emergence of resistance to other drugs.

Dataset Information

Functionalized Dioxonaphthoimidazoliums: A Redox Cycling Chemotype with Potent Bactericidal Activities against Mycobacterium tuberculosis.

Publications

Functionalized Dioxonaphthoimidazoliums: A Redox Cycling Chemotype with Potent Bactericidal Activities against <i>Mycobacterium tuberculosis</i>.

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