Efflux Inhibition with Verapamil Potentiates Bedaquiline in Mycobacterium tuberculosis

Gupta, Shashank; Cohen, Keira A.; Winglee, Kathryn; Maiga, Mamoudou; Diarra, Bassirou; Bishai, William R.

doi:10.1128/aac.01462-13

Cited by 143 publications

(109 citation statements)

References 16 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Importantly, all 12 patients who had a post-baseline ⩾4-fold increase in bedaquiline MIC had mutations in Rv0678, a transcriptional repressor of the MmpS5-MmpL5 efflux pump [25]. Recently, this novel efflux mechanism of resistance has been identified to result in low-level resistance to bedaquiline and clofazimine [25,29,30]. The current data do not suggest that increases in bedaquiline MICs due to mutations in Rv0678 have a negative effect on treatment response.…”

Section: Discussionmentioning

confidence: 62%

Bedaquiline in the treatment of multidrug- and extensively drug-resistant tuberculosis

Pym¹,

et al. 2015

View full text Add to dashboard Cite

Bedaquiline, a diarylquinoline, improved cure rates when added to a multidrug-resistant tuberculosis (MDR-TB) treatment regimen in a previous placebo-controlled, phase 2 trial (TMC207-C208; NCT00449644). The current phase 2, multicenter, open-label, single-arm trial (TMC207-C209; NCT00910871) reported here was conducted to confirm the safety and efficacy of bedaquiline.Newly diagnosed or previously treated patients with MDR-TB (including pre-extensively drug-resistant (pre-XDR)-TB or extensively drug-resistant (XDR)-TB) received bedaquiline for 24 weeks with a background regimen of anti-TB drugs continued according to National TB Programme treatment guidelines. Patients were assessed during and up to 120 weeks after starting bedaquiline.Of 233 enrolled patients, 63.5% had MDR-TB, 18.9% had pre-XDR-TB and 16.3% had XDR-TB, with 87.1% having taken second-line drugs prior to enrolment. 16 patients (6.9%) died. 20 patients (8.6%) discontinued before week 24, most commonly due to adverse events or MDR-TB-related events. Adverse events were generally those commonly associated with MDR-TB treatment. In the efficacy population (n=205), culture conversion (missing outcome classified as failure) was 72.2% at 120 weeks, and 73.1%, 70.5% and 62.2% in MDR-TB, pre-XDR-TB and XDR-TB patients, respectively.Addition of bedaquiline to a background regimen was well tolerated and led to good outcomes in this clinically relevant patient cohort with MDR-TB. @ERSpublications Bedaquiline safety data in a broad patient population treated for drug-resistant TB including XDR-TB (C209 study)

show abstract

Section: Discussionmentioning

confidence: 62%

Bedaquiline in the treatment of multidrug- and extensively drug-resistant tuberculosis

Pym¹,

et al. 2015

View full text Add to dashboard Cite

show abstract

“…Furthermore, verapamil adjunctive therapy in the rodent model was shown to accelerate bactericidal activity and achieve durable sterilization (10). Moreover, Gupta et al showed that verapamil was able to decrease the MIC of bedaquiline and clofazimine by 8-to 16-fold, which was further confirmed in vivo using a mouse model (11,12).…”

mentioning

confidence: 69%

“…Moxifloxacin was used as a negative control because its activity, as measured in vitro, was previously unaffected by verapamil. Bedaquiline was included as a positive control because the combination of bedaquiline and verapamil showed greater activity against M. tuberculosis in vitro compared with that of bedaquiline alone due to efflux pump inhibition (11). As shown in Fig.…”

Section: Resultsmentioning

confidence: 99%

Efflux Attenuates the Antibacterial Activity of Q203 in Mycobacterium tuberculosis

Jang

Kim

Woo

et al. 2017

Antimicrob Agents Chemother

View full text Add to dashboard Cite

New and improved treatments for tuberculosis (TB) are urgently needed.Recently, it has been demonstrated that verapamil, an efflux inhibitor, can reduce bacterial drug tolerance caused by efflux pump activity when administered in combination with available antituberculosis agents. The aim of this study was to evaluate the effectiveness of verapamil in combination with the antituberculosis drug candidate Q203, which has recently been developed and is currently under clinical trials as a potential antituberculosis agent. We evaluated changes in Q203 activity in the presence and absence of verapamil in vitro using the resazurin microplate assay and ex vivo using a microscopy-based phenotypic assay for the quantification of intracellular replicating mycobacteria. Verapamil increased the potency of Q203 against Mycobacterium tuberculosis both in vitro and ex vivo, indicating that efflux pumps are associated with the activity of Q203. Other efflux pump inhibitors also displayed an increase in Q203 potency, strengthening this hypothesis. Therefore, the combination of verapamil and Q203 may be a promising combinatorial strategy for anti-TB treatment to accelerate the elimination of M. tuberculosis.

show abstract

“…It would be interesting to test whether AcrZ is involved in resistance to the fatty acids and bile salts among the suggested ecological substrates of AcrB, particularly considering that acrZ is regulated by a transcription factor that is sensitive to these compounds (14,15). Studies elucidating the ecologically relevant or endogenous inducers and substrates of efflux pumps will ultimately help us to better understand their evolution, maintenance in diverse genomes, and critical roles in the physiology of pathogens and malignant host cells (58)(59)(60).…”

Section: Discussionmentioning

confidence: 99%

The Pseudomonas aeruginosa efflux pump MexGHI-OpmD transports a natural phenazine that controls gene expression and biofilm development

Sakhtah

Koyama

Zhang

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

138

159

View full text Add to dashboard Cite

Redox-cycling compounds, including endogenously produced phenazine antibiotics, induce expression of the efflux pump MexGHIOpmD in the opportunistic pathogen Pseudomonas aeruginosa. Previous studies of P. aeruginosa virulence, physiology, and biofilm development have focused on the blue phenazine pyocyanin and the yellow phenazine-1-carboxylic acid (PCA). In P. aeruginosa phenazine biosynthesis, conversion of PCA to pyocyanin is presumed to proceed through the intermediate 5-methylphenazine-1-carboxylate (5-Me-PCA), a reactive compound that has eluded detection in most laboratory samples. Here, we apply electrochemical methods to directly detect 5-Me-PCA and find that it is transported by MexGHIOpmD in P. aeruginosa strain PA14 planktonic and biofilm cells. We also show that 5-Me-PCA is sufficient to fully induce MexGHI-OpmD expression and that it is required for wild-type colony biofilm morphogenesis. These physiological effects are consistent with the high redox potential of 5-Me-PCA, which distinguishes it from other well-studied P. aeruginosa phenazines. Our observations highlight the importance of this compound, which was previously overlooked due to the challenges associated with its detection, in the context of P. aeruginosa gene expression and multicellular behavior. This study constitutes a unique demonstration of efflux-based selfresistance, controlled by a simple circuit, in a Gram-negative pathogen.phenazine | RND efflux | MexGHI-OpmD | biofilm | antibiotic

show abstract

Efflux Inhibition with Verapamil Potentiates Bedaquiline in Mycobacterium tuberculosis

Cited by 143 publications

References 16 publications

Bedaquiline in the treatment of multidrug- and extensively drug-resistant tuberculosis

Bedaquiline in the treatment of multidrug- and extensively drug-resistant tuberculosis

Efflux Attenuates the Antibacterial Activity of Q203 in Mycobacterium tuberculosis

The Pseudomonas aeruginosa efflux pump MexGHI-OpmD transports a natural phenazine that controls gene expression and biofilm development

Contact Info

Product

Resources

About