Synergistic Response of Rifampicin with Hydroperoxides on Mycobacterium: A Mechanistic Study

Patel, Yesha; Mehra, Sarika

doi:10.3389/fmicb.2017.02075

Cited by 17 publications

(15 citation statements)

References 76 publications

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“…Furthermore, to check the importance of ROS in bacteria, cells were treated with an antioxidant, ascorbic acid . If ROS was involved in the inhibitory action of ZnO NPs and RIF, the inhibitory effect should be lost upon the addition of ascorbic acid . The MIC of ascorbic acid was found to be 6400 μg/mL.…”

Section: Resultsmentioning

confidence: 99%

“…A 50:50 mixture of acetonitrile and acidified water at pH 2.27 with orthophosphoric acid was used as a mobile phase. The flow rate used was 1.2 mL/min, and eluted RIF was measured with a UV detector at 333 nm …”

Section: Materials and Methodsmentioning

confidence: 99%

“…The flow rate used was 1.2 mL/min, and eluted RIF was measured with a UV detector at 333 nm. 38 3. RESULTS AND DISCUSSION 3.1.…”

Section: Zn(ch Coo) 2h O 2naohmentioning

confidence: 99%

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ZnO Nanoparticles and Rifampicin Synergistically Damage the Membrane of Mycobacteria

Mistry

Bandyopadhyaya

Mehra

2020

ACS Appl. Nano Mater.

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The emergence of drug resistance in tuberculosis requires alternative strategies to combat the resistance. To this end, we have synthesized zinc oxide nanoparticles (ZnO NPs) of 11 nm diameter and evaluated its effect against mycobacteria alone, as well as in combination with the first-line anti-TB drug, rifampicin. These ZnO NPs themselves are not inhibitory against the wild-type (WT) Mycobacterium smegmatis, up to a concentration as high as 256 μg/mL. However, a subinhibitory concentration of only 32 μg/mL of ZnO NPs in combination with rifampicin, showed a 4-fold reduction in the minimum inhibitory concentration of rifampicin, against WT M. smegmatis. Thus, the fractional inhibitory concentration index for the combination was found to be 0.375, which proves the effect to be synergistic. This is explained by high membrane permeability observed in presence of the combination of ZnO NPs and rifampicin, which increased with time. High membrane permeability, in turn, increased rifampicin uptake in cells, which subsequently enhanced the bactericidal effect of the drug. The resultant morphology of the bacteria, from Cryo-SEM, showed membrane damage, following treatment with a combination of ZnO NPs and rifampicin. However, this combination showed very less reactive oxygen species (ROS) production, compared to ZnO NPs alone. Hence, we can conclude that membrane damage is the dominant mechanism behind synergism of the combination, rather than that of ROS generation. This combination also proved to be successful against our laboratory-generated, drug resistant strains of M. smegmatis, as well as against vaccine strain- M. bovis BCG, which proves the general applicability of this synergism for different strains. We hence propose that our developed ZnO NPs and drug combination can be promising for overcoming mycobacterial drug resistance.

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Section: Resultsmentioning

confidence: 99%

Section: Materials and Methodsmentioning

confidence: 99%

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ZnO Nanoparticles and Rifampicin Synergistically Damage the Membrane of Mycobacteria

Mistry

Bandyopadhyaya

Mehra

2020

ACS Appl. Nano Mater.

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“…The conversion of resazurin (blue/purple) to resorufin (red/pink) is a direct indication of mycobacterial viability. The minimum concentration at which no growth was observed visually was taken as the MIC . The FICI for each compound was calculated as follows .

normalFIC = \frac{normalMIC ([], A) normalcombination}{normalMIC ([], A) normalalone} + \frac{normalMIC ([], B) normalcombination}{normalMIC ([], B) normalalone}

…”

Section: Methodsmentioning

confidence: 99%

The evaluation of the anti‐cancer drug elesclomol that forms a redox‐active copper chelate as a potential anti‐tubercular drug

et al. 2019

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The observations that the innate immune system employs copper to eliminate bacterial infection and that resistance to copper enhances virulence of Mycobacterium tuberculosis (Mtb) prompted us to examine the effects the anti‐cancer agent elesclomol on Mtb. As a bis‐thionohydrazide, elesclomol chelates with copper to form a copper complex in situ that via redox cycling of the metal ion greatly enhances oxidative stress in tumour cells. Here, we demonstrate that elesclomol is relatively potent against Mtb H37Rv with minimum inhibitory concentration of 10 μM (4 mg/L) and against multidrug resistant clinical isolates of Mtb, displays additive interactions with known tuberculosis drugs such as isoniazid and ethambutol, and a synergistic interaction with rifampicin. Controlled supplementation of elesclomol with copper in culture medium increased Mtb sensitivity by >65 fold. Overall, the activities of elesclomol in principle indicate the possibility of repurposing elesclomol or designing new thionohydrazides as potential drugs for use against Mtb. © 2019 IUBMB Life, 71(5):532–538, 2019

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“…MIC of RIF reduced from 0.015 to 0.00048 mg/mL when given in combination with antitubercular drug SQ109 against M. tuberculosis strain H37R V [60]. Cumene hydroperoxide reduced the MIC of RIF by 16-fold against M. tuberculosis strain H37R V [61].…”

Section: Plos Onementioning

confidence: 96%

Inhibitory activity of traditional plants against Mycobacterium smegmatis and their action on Filamenting temperature sensitive mutant Z (FtsZ)—A cell division protein

et al. 2020

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The study was designed to assess whether plant extracts / phytochemical (D-Pinitol) synergistically combine with antituberculosis drugs and act on Mycobacterium smegmatis (M. smegmatis) as well as assess their mode of action on Mycobacterium tuberculosis (M.tb) Filamenting temperature sensitive mutant Z (FtsZ) protein. Resazurin microtitre plate assay (Checker board) was performed to analyze the activity of plant extracts against M. smegmatis. Synergistic behaviour of plant extracts / D-Pinitol with Isoniazid (INH) and Rifampicin (RIF) were determined by time-kill and checker board assays. Elongation of M. smegmatis cells due to this treatment was determined by light microscopy. The effect of Hexane methanol extract (HXM) plant extracts on cell viability was determined using PI/SYTO9 dual dye reporter Live/Dead assay. Action of HXM plant extracts / D-Pinitol on inhibition of FtsZ protein was done using Guanosine triphosphatase (GTPase) light scattering assay and quantitative Polymerase Chain Reaction (qPCR). The Hexane-methanolic plant extract of Acacia nilotica, Aegle marmelos and Glycyrrhiza glabra showed antimycobacterial activity at 1.56 ± 0.03, 1.32 ± 0.02 and 1.25 ± 0.03 mg/ mL respectively and that of INH and RIF were 4.00 ± 0.06 μg/mL and 2.00 ± 0.04 μg/mL respectively. These plant extracts and major phytochemical exudate D-Pinitol was found to act synergistically with antimycobacterial drugs INH and RIF with an FIC index~0.20. Time-Kill kinetics studies indicate that, these plant extracts were bacteriostatic in nature. D-Pinitol in conjunction with INH and RIF exhibited a 2 Log reduction in the growth of viable cells compared to untreated. Attempt to elucidate their mode of action through phenotypic analysis indicated that these plant extracts and D-Pinitol was found to interfere in cell division there by leading to an abnormal elongated cellular morphology. HXM extracts and D-Pinitol synergistically combined with the first line tuberculosis drugs, INH and RIF, to act on M. smegmatis. The increase in the length of M. smegmatis cells on treatment with D-Pinitol and HXM extract of the plants indicated that they hinder the cell division mechanism thereby leading to a filamentous phenotype, and finally leading to cell death. In addition, the integrity of the bacterial cell membrane is also altered causing cell death. Further gene expression analysis showed that these plant extracts and D-Pinitol hampers

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Synergistic Response of Rifampicin with Hydroperoxides on Mycobacterium: A Mechanistic Study

Cited by 17 publications

References 76 publications

ZnO Nanoparticles and Rifampicin Synergistically Damage the Membrane of Mycobacteria

ZnO Nanoparticles and Rifampicin Synergistically Damage the Membrane of Mycobacteria

The evaluation of the anti‐cancer drug elesclomol that forms a redox‐active copper chelate as a potential anti‐tubercular drug

Inhibitory activity of traditional plants against Mycobacterium smegmatis and their action on Filamenting temperature sensitive mutant Z (FtsZ)—A cell division protein

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