In vitro evaluation of dinactin, a potent microbial metabolite against Mycobacterium tuberculosis

Hussain, Aashiq; Rather, Muzafar Ahmad; Bhat, Zubair Shanib; Majeed, Aasif; Maqbool, Mubashir; Shah, Aabid Manzoor; Aga, Mushtaq A.; Shah, Aabid Manzoor; Mushtaq, Saleem; Sangwan, Payare L.; Hassan, Qazi Parvaiz; Ahmad, Zahoor

doi:10.1016/j.ijantimicag.2018.09.019

Cited by 18 publications

(9 citation statements)

References 32 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Only dinactin exhibited potent inhibitory activity against M. tuberculosis H37Rv with a MIC of 0.5µg/ml (Fig. 1C), consistent with previous reports (Hussain et al, 2019).…”

Section: Resultssupporting

confidence: 92%

“…and the biosynthesis of dinactin was rst studied in 2016 when the involvement of the nonS gene encoding for the closure of the tetrahydrofuran ring in dinactin biosynthesis was proposed (He et al, 2016). Despite dinactin has been described as a lead compound with signi cant activity against both drugsusceptible and -resistant M. tuberculosis (Hussain et al, 2019), the action of dinactin against M. tuberculosis has not yet been clari ed, and its potential effect as an antituberculosis drug has not been evaluated.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Naturally occurring Dinactin targets cpsA of LytR-Cps2A-Psr family protein as well as kills Mycobacterium tuberculosis by disrupting proton motive force

Tan

Yan

Dong

et al. 2023

Preprint

View full text Add to dashboard Cite

Tuberculosis is still a global threat, and new drugs are desperately needed to combat the spread of multidrug-resistant Mycobacterium tuberculosis. Historically, natural products have been an important source of drugs against infectious diseases, like tuberculosis. Here, we identified a natural macrotetrolide dinactin with antituberculosis activity against susceptible and non-replicating Mycobacterium tuberculosis. Dinactin can synergistically enhance the antituberculosis effect of rifampicin and isoniazide against wild-type and drug-resistant strains. Dinactin also demonstrates antituberculosis activity in macrophage and Galleria mellonella models. Interestingly, dinactin possesses the properties of the ionophore. It not only enhances cations transport across the cell membrane and can alter membrane permeability but also causes the dissipation of proton motive force and metabolic perturbations. By selecting spontaneous resistant mutants and whole genome sequencing, we successfully identified non-synonymous single nucleotide polymorphisms in the cpsA gene of the LytR-Cps2A-Psr family. The dinactin-resistant mutants decrease the in vitro drug sensitivity to dinactin without cross-resistant with first-line antituberculosis drugs. Subsequently, genetic studies and molecular biology assays confirm the cpsA as the principal target. These findings suggest that dinactin could be a promising antibiotic for treating drug-resistant tuberculosis.

show abstract

“…Only dinactin exhibited potent inhibitory activity against M. tuberculosis H37Rv with a MIC of 0.5µg/ml (Fig. 1C), consistent with previous reports (Hussain et al, 2019).…”

Section: Resultssupporting

confidence: 92%

Section: Introductionmentioning

confidence: 99%

Naturally occurring Dinactin targets cpsA of LytR-Cps2A-Psr family protein as well as kills Mycobacterium tuberculosis by disrupting proton motive force

Tan

Yan

Dong

et al. 2023

Preprint

View full text Add to dashboard Cite

show abstract

“…Isoniazid and RIF, two known anti-TB drugs demonstrated strong synergism as indicated by their ΣFIC values. This phenomenon is the basis of the short-lived effect of modern TB treatment in humans [19,20]. The combination of compound j with RIF, LVX or AMK exhibited additive drug-drug interactions.…”

Section: Antimycobacterial Effects Of Pyridone Analogsmentioning

confidence: 98%

<I>In vitro</I> evaluation of the inhibitory effect of 3, 5-dichloro-2- pyridone on <I>Mycobacterium tuberculosis</I> H37Rv

Lin¹,

Ling²,

Wu³

2020

Trop. J. Pharm Res

View full text Add to dashboard Cite

Purpose: To investigate the anti-tuberculosis potential of twelve commercially available pyridone analogues against Mycobacterium tuberculosis H37Rv strain.Methods: Twelve commercially available pyridone-based compounds were screened against M. tuberculosis H37Rv using different susceptibility tests. The most active or lead compound was further evaluated in detail for its anti-tuberculosis (anti-TB) potential. Kill kinetics was used to determine the dynamics of its anti-TB activity in vitro.Results: Compounds d, j and k were potent against M. tuberculosis H37Rv, with minimum inhibitory concentrations (MICs) of 10, 5 and 10 μg/mL, respectively. The standard anti-TB drugs used in this study (positive control drugs) demonstrated MIC of 2.5 μg/mL. The anti-TB effect of compound j was comparable with those of the standard drugs (RIF, LVX, AMK, EMB and INH). The minimum bactericidal concentration (MBC) of compound j was 10 μg/mL. It produced an MIC of 5 μg/mL in agar proportion method (APM). However, its MIC in Middlebrook 7H9 broth supplemented with 10 % fetal bovine serum (FBS) and 4 % bovine serum albumin (BSA) increased 4- and 8-fold, respectively. The bactericidal effect of compound j was time- and concentration-dependent at dilutions above 2x MIC. Combination of compound j with RIF, LVX or AMK exhibited fractional inhibitory concentration index (ΣFIC) of 1, indicative of additive drug-drug interactions. However, combination with INH or EMB produced a ΣFIC of 2. None of the tested drug combinations was antagonistic.Conclusion: Compound j exhibits potent time- and concentration-dependent antimicrobial effect against M. tuberculosis H37Rv. Thus, it may be suitable as an adjunct to current treatment of drug sensitive and drug-resistant TB. Keywords: Tuberculosis, Mycobacterium tuberculosis, Pyridone analogs, Antimicrobial activity, Antibiotics

show abstract

“…Drug stock solutions were dissolved in Middlebrook 7H9 broth (consisting of 10%ADC) in the absence of Tween 80. Drug solutions were made in 96-well plates (Nest Biotech, China), employing two-fold serial dilutions so that the test compounds concentrations ranged from 0.125 to 128 µg/mL while maintaining a growth and media control column (200 µl in each well) [27]. Except for the media control column, an equivalent volume (50 µl) of bacterial inoculum comprising mid-log phase growing M. tuberculosis was added so that the final cell density in each well equals approximately 1x10 5 CFU/mL.…”

Section: • Determination Of Minimum Inhibitory Concentration (Mic) Ag...mentioning

confidence: 99%

Antituberculosis Propensity of Synthetic Biscoumarin Derivatives: An In Silico and In Vitro Approach

Sheikh¹,

Bhat²,

Zareen³

et al. 2023

Preprint

View full text Add to dashboard Cite

The concerning rise in emergence and prevalence of resistant strains to drugs of M. tuberculosis has ,the prompted researchers to look for new and effective treatments. With this motive, biscoumarins were identified as the lead molecules on a whole-cell-based screening of several less explored low molecular weight bioactive compounds against M. tuberculosis strains. Among the screened biscoumarins, the highest dock score derivatives were synthesized (a-h) using a programmable microwave synthesizer for better yields and reaction control. The synthesized derivatives were evaluated against H37Rv, H37Ra, M. smegmatis, an MDR surrogate model, and other bacterial strains for the structure-activity response. Assessment of the synthesized library against mycobacterial strains led to the identification of compounds (f and d) as lead anti-tuberculosis agents. Compounds (f and d) exhibited less toxicity against human cell lines. At the same time, it displayed enjoyable activity wherein MIC concentrations were observed to be 16- and 32 µg/mL against the susceptible H37Rv, and H37Ra strains of M. tuberculosis and MIC value of 128 µg/mL for M. smegmatis, respectively. For mechanistic insights and identification of drug binding targets, molecular docking and dynamic simulations were employed for a panel of 16 mycobacterial enzymes essential for mycobacterial growth and survival. These in silico studies revealed the DprE1 enzyme as a druggable target for the anti-tuberculosis activity of the selected biscoumarins derivatives. Further investigation is underway in our laboratory, leading to its development as an anti-tuberculosis drug (animal model studies).

show abstract

In vitro evaluation of dinactin, a potent microbial metabolite against Mycobacterium tuberculosis

Cited by 18 publications

References 32 publications

Naturally occurring Dinactin targets cpsA of LytR-Cps2A-Psr family protein as well as kills Mycobacterium tuberculosis by disrupting proton motive force

Naturally occurring Dinactin targets cpsA of LytR-Cps2A-Psr family protein as well as kills Mycobacterium tuberculosis by disrupting proton motive force

<I>In vitro</I> evaluation of the inhibitory effect of 3, 5-dichloro-2- pyridone on <I>Mycobacterium tuberculosis</I> H37Rv

Antituberculosis Propensity of Synthetic Biscoumarin Derivatives: An In Silico and In Vitro Approach

Contact Info

Product

Resources

About