Резерпин как еще один ингибитор трансмембранного эффлюксного насоса AcrB

Shaheen, Aqsa; Afridi, Waqar Ahmed; Mahboob, Sadia; Sana, Maryam; Zeeshan, Nadia; Ismat, Fouzia; Mirza, Osman; Iqbal, Mazhar; Rahman, Mahmuder

doi:10.1134/s0026898419040128

Cited by 8 publications

(1 citation statement)

References 43 publications

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“…It is noteworthy that the controls also showed a better predicted affinity towards the AcrB portion. Recently, reserpine was described as an AcrB inhibitor [ 28 ], and the docking study suggested the SBS as one of the binding sites for reserpine. Taking into account the docking results, we chose to study the efflux modulation of a model without the AcrA portion, as this was predicted to be the portion to which the compounds presented the least affinity.…”

Section: Resultsmentioning

confidence: 99%

Xanthones Active against Multidrug Resistance and Virulence Mechanisms of Bacteria

et al. 2021

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The emergence of multidrug and extensively drug-resistant pathogenic bacteria able to resist to the action of a wide range of antibiotics is becoming a growing problem for public health. The search for new compounds with the potential to help in the reversion of bacterial resistance plays an important role in current medicinal chemistry research. Under this scope, bacterial efflux pumps are responsible for the efflux of antimicrobials, and their inhibition could reverse resistance. In this study, the multidrug resistance reversing activity of a series of xanthones was investigated. Firstly, docking studies were performed in the AcrAB-TolC efflux pump and in a homology model of the NorA pump. Then, the effects of twenty xanthone derivatives on bacterial growth were evaluated in Staphylococcus aureus 272123 and in the acrA gene-inactivated mutant Salmonella enterica serovar Typhimurium SL1344 (SE03). Their efflux pump inhibitory properties were assessed using real-time fluorimetry. Assays concerning the activity of these compounds towards the inhibition of biofilm formation and quorum sensing have also been performed. Results showed that a halogenated phenylmethanamine xanthone derivative displayed an interesting profile, as far as efflux pump inhibition and biofilm formation were concerned. To the best of our knowledge, this is the first report of xanthones as potential efflux pump inhibitors.

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Section: Resultsmentioning

confidence: 99%

Xanthones Active against Multidrug Resistance and Virulence Mechanisms of Bacteria

et al. 2021

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The human proton pump inhibitors inhibit Mycobacterium tuberculosis rifampicin efflux and macrophage-induced rifampicin tolerance

Lake

Adams

Nie

et al. 2023

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

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Tuberculosis treatment requires months-long combination chemotherapy with multiple drugs, with shorter treatments leading to relapses. A major impediment to shortening treatment is that Mycobacterium tuberculosis becomes tolerant to the administered drugs, starting early after infection and within days of infecting macrophages. Multiple lines of evidence suggest that macrophage-induced drug tolerance is mediated by mycobacterial drug efflux pumps. Here, using assays to directly measure drug efflux, we find that M. tuberculosis transports the first-line antitubercular drug rifampicin through a proton gradient-dependent mechanism. We show that verapamil, a known efflux pump inhibitor, which inhibits macrophage-induced rifampicin tolerance, also inhibits M.tuberculosis rifampicin efflux. As with macrophage-induced tolerance, the calcium channel-inhibiting property of verapamil is not required for its inhibition of rifampicin efflux. By testing verapamil analogs, we show that verapamil directly inhibits M. tuberculosis drug efflux pumps through its human P-glycoprotein (PGP)-like inhibitory activity. Screening commonly used drugs with incidental PGP inhibitory activity, we find many inhibit rifampicin efflux, including the proton pump inhibitors (PPIs) such as omeprazole. Like verapamil, the PPIs inhibit macrophage-induced rifampicin tolerance as well as intramacrophage growth, which has also been linked to mycobacterial efflux pump activity. Our assays provide a facile screening platform for M. tuberculosis efflux pump inhibitors that inhibit in vivo drug tolerance and growth.

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Tripartite efflux pumps of the RND superfamily: what did we learn from computational studies?

et al. 2023

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Bacterial resistance to antibiotics has been long recognized as a priority to address for human health. Among all micro-organisms, the so-called multi-drug resistant (MDR) bacteria, which are resistant to most, if not all drugs in our current arsenal, are particularly worrisome. The World Health Organization has prioritized the ESKAPE ( Enterococcus faecium , Staphylococcus aureus , Klebsiella pneumoniae , Acinetobacter baumannii , Pseudomonas aeruginosa and Enterobacter species) pathogens, which include four Gram-negative bacterial species. In these bacteria, active extrusion of antimicrobial compounds out of the cell by means of ‘molecular guns’ known as efflux pumps is a main determinant of MDR phenotypes. The resistance-nodulation-cell division (RND) superfamily of efflux pumps connecting the inner and outer membrane in Gram-negative bacteria is crucial to the onset of MDR and virulence, as well as biofilm formation. Thus, understanding the molecular basis of the interaction of antibiotics and inhibitors with these pumps is key to the design of more effective therapeutics. With the aim to contribute to this challenge, and complement and inspire experimental research, in silico studies on RND efflux pumps have flourished in recent decades. Here, we review a selection of such investigations addressing the main determinants behind the polyspecificity of these pumps, the mechanisms of substrate recognition, transport and inhibition, as well as the relevance of their assembly for proper functioning, and the role of protein–lipid interactions. The journey will end with a perspective on the role of computer simulations in addressing the challenges posed by these beautifully complex machineries and in supporting the fight against the spread of MDR bacteria.

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Резерпин как еще один ингибитор трансмембранного эффлюксного насоса AcrB

Cited by 8 publications

References 43 publications

Xanthones Active against Multidrug Resistance and Virulence Mechanisms of Bacteria

Xanthones Active against Multidrug Resistance and Virulence Mechanisms of Bacteria

The human proton pump inhibitors inhibit Mycobacterium tuberculosis rifampicin efflux and macrophage-induced rifampicin tolerance

Tripartite efflux pumps of the RND superfamily: what did we learn from computational studies?

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