Efficacy of β-lactam/β-lactamase inhibitor combination is linked to WhiB4-mediated changes in redox physiology of Mycobacterium tuberculosis

Mishra, Saurabh; Shukla, Prashant; Bhaskar, Ashima; Anand, Kuljeet Singh; Baloni, Priyanka; Jha, Rajiv Kumar; Mohan, Abhilash; Rajmani, Raju S; Nagaraja, Valakunja; Chandra, Nagasuma; Singh, Amit

doi:10.7554/elife.25624

Cited by 53 publications

(49 citation statements)

References 83 publications

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“…Mouse infection and isolation of exosomes from serum and lungs. BALB/c mice (6 to 8 weeks old) were infected with M. tuberculosis 100 bacilli per lung by aerosol or left uninfected as described previously (100). At 20 weeks p.i., animals were euthanized and serum and lungs were collected.…”

Section: Methodsmentioning

confidence: 99%

Mycobacterium tuberculosis Reactivates HIV-1 via Exosome-Mediated Resetting of Cellular Redox Potential and Bioenergetics

Tyagi

Pal

Agrawal

et al. 2020

mBio

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The synergy between Mycobacterium tuberculosis and human immunodeficiency virus-1 (HIV-1) interferes with therapy and facilitates the pathogenesis of both human pathogens. Fundamental mechanisms by which M. tuberculosis exacerbates HIV-1 infection are not clear. Here, we show that exosomes secreted by macrophages infected with M. tuberculosis, including drug-resistant clinical strains, reactivated HIV-1 by inducing oxidative stress. Mechanistically, M. tuberculosis-specific exosomes realigned mitochondrial and nonmitochondrial oxygen consumption rates (OCR) and modulated the expression of host genes mediating oxidative stress response, inflammation, and HIV-1 transactivation. Proteomics analyses revealed the enrichment of several host factors (e.g., HIF-1␣, galectins, and Hsp90) known to promote HIV-1 reactivation in M. tuberculosis-specific exosomes. Treatment with a known antioxidant-N-acetyl cysteine (NAC)-or with inhibitors of host factors-galectins and Hsp90 -attenuated HIV-1 reactivation by M. tuberculosis-specific exosomes. Our findings uncover new paradigms for understanding the redox and bioenergetics bases of HIV-M. tuberculosis coinfection, which will enable the design of effective therapeutic strategies. IMPORTANCE Globally, individuals coinfected with the AIDS virus (HIV-1) and with M. tuberculosis (causative agent of tuberculosis [TB]) pose major obstacles in the clinical management of both diseases. At the heart of this issue is the apparent synergy between the two human pathogens. On the one hand, mechanisms induced by HIV-1 for reactivation of TB in AIDS patients are well characterized. On the other hand, while clinical findings clearly identified TB as a risk factor for HIV-1 reactivation and associated mortality, basic mechanisms by which M. tuberculosis exacerbates HIV-1 replication and infection remain poorly characterized. The significance of our research is in identifying the role of fundamental mechanisms such as redox and energy metabolism in catalyzing HIV-M. tuberculosis synergy. The quantification of redox and respiratory parameters affected by M. tuberculosis in stimulating HIV-1 will greatly enhance our understanding of HIV-M. tuberculosis coinfection, leading to a wider impact on the biomedical research community and creating new translational opportunities.

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Section: Methodsmentioning

confidence: 99%

Mycobacterium tuberculosis Reactivates HIV-1 via Exosome-Mediated Resetting of Cellular Redox Potential and Bioenergetics

Tyagi

Pal

Agrawal

et al. 2020

mBio

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“…The notorious tendency of M. tuberculosis with the conjunction of prolonged treatment regimens shows drug resistant which is developed in different stages (Connolly et al 2007). Also the expression of β-lactamase is considered as the most significant causes for developing intrinsic resistant to these antibiotics (Mishra et al 2017). In line with this context, recent studies reported that the sensitivity to M. tuberculosis is increased by 8-256 fold upon the deletion of chromosomal class A (Ambler)…”

Section: Introductionmentioning

confidence: 98%

Molecular docking and dynamics of Nickel-Schiff base complexes for inhibiting β-lactamase of Mycobacterium tuberculosis

Junaid¹,

Alam²,

Hossain³

et al. 2018

In Silico Pharmacol.

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In recent years, multidrug-resistance has become a primary concern in the treatment and management of tuberculosis, an infectious disease caused by Mycobacterium tuberculosis. In this context, searching new anti-tuberculosis agents particularly targeting the β-lactamase (BlaC) is reported to be promising as this enzyme is one of the key player in the development of multidrug resistance. This study reports the design of some Nickel (Ni) based tetradentate N 2 O 2 Schiff bases, employing density functional theory. All analogs are optimized at B3LYP/SDD level of theory. Dipole moment, electronic energy, enthalpy, Gibbs free energy, HOMO-LUMO gap, and softness of these modified drugs are also investigated. Molecular interactions between designed ligands and BlaC have been analyzed by molecular docking approach, followed by molecular dynamics (MD) simulation. All designed compounds show low HOMO-LUMO gap, while addition of halogen increases the dipole moment of the compounds. Docking and MD simulation investigations reveal that the designed compounds are more potent than standard inhibitor, where Ile117, Pro290, Arg236 and Thr253 residues of BlaC are found to play important role in the ligand binding. Through MD simulation study, the best binding compound is also observed to form stable complex by increasing the protein rigidness. The ADME/T analysis suggests that modified drugs are less toxic and shows an improved pharmacokinetic properties than that of the standard drug. These results further confirm the ability of Ni-directed Schiff bases to bind simultaneously to the active site of BlaC and support them as potential candidates for the future treatment of tuberculosis disease.

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“…Using Mrx1-roGFP2, E MSH changes were studied in drug-resistant Mtb isolates, during intracellular replication and persistence in the acidic phagosomes of macrophages [36] , [37] , [38] . Mrx1-roGFP2 was also applied as tool in drug research to screen for ROS-generating anti-tuberculosis drugs or to reveal the mode of action of combination therapies based on E MSH changes [36] , [39] , [40] , [41] . The Mtb population exhibited redox heterogeneity of E MSH during infection inside macrophages which was dependent on sub-vacuolar compartments and the cytoplasmic acidification controlled by WhiB3 [36] , [38] .…”

Section: Introductionmentioning

confidence: 99%

Stable integration of the Mrx1-roGFP2 biosensor to monitor dynamic changes of the mycothiol redox potential in Corynebacterium glutamicum

et al. 2019

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Mycothiol (MSH) functions as major low molecular weight (LMW) thiol in the industrially important Corynebacterium glutamicum. In this study, we genomically integrated an Mrx1-roGFP2 biosensor in C. glutamicum to measure dynamic changes of the MSH redox potential (EMSH) during the growth and under oxidative stress. C. glutamicum maintains a highly reducing intrabacterial EMSH throughout the growth curve with basal EMSH levels of ~− 296 mV. Consistent with its H2O2 resistant phenotype, C. glutamicum responds only weakly to 40 mM H2O2, but is rapidly oxidized by low doses of NaOCl. We further monitored basal EMSH changes and the H2O2 response in various mutants which are compromised in redox-signaling of ROS (OxyR, SigH) and in the antioxidant defense (MSH, Mtr, KatA, Mpx, Tpx). While the probe was constitutively oxidized in the mshC and mtr mutants, a smaller oxidative shift in basal EMSH was observed in the sigH mutant. The catalase KatA was confirmed as major H2O2 detoxification enzyme required for fast biosensor re-equilibration upon return to non-stress conditions. In contrast, the peroxiredoxins Mpx and Tpx had only little impact on EMSH and H2O2 detoxification. Further live imaging experiments using confocal laser scanning microscopy revealed the stable biosensor expression and fluorescence at the single cell level. In conclusion, the stably expressed Mrx1-roGFP2 biosensor was successfully applied to monitor dynamic EMSH changes in C. glutamicum during the growth, under oxidative stress and in different mutants revealing the impact of Mtr and SigH for the basal level EMSH and the role of OxyR and KatA for efficient H2O2 detoxification under oxidative stress.

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Efficacy of β-lactam/β-lactamase inhibitor combination is linked to WhiB4-mediated changes in redox physiology of Mycobacterium tuberculosis

Cited by 53 publications

References 83 publications

Mycobacterium tuberculosis Reactivates HIV-1 via Exosome-Mediated Resetting of Cellular Redox Potential and Bioenergetics

Mycobacterium tuberculosis Reactivates HIV-1 via Exosome-Mediated Resetting of Cellular Redox Potential and Bioenergetics

Molecular docking and dynamics of Nickel-Schiff base complexes for inhibiting β-lactamase of Mycobacterium tuberculosis

Stable integration of the Mrx1-roGFP2 biosensor to monitor dynamic changes of the mycothiol redox potential in Corynebacterium glutamicum

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