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Updated: Aug 13, 2026
In vitro Investigation of the MexAB Efflux Pump From Pseudomonas aeruginosa
Published on: February 17, 2014
Protonation Based Molecular Mechanism Behind Rv0191 Efflux Transporter Conferring Pyrazinamide Resistance in
Deepti Dhusia1, Garima Singh1, Dinesh Raj Modi1
1Department of Biotechnology, Babasaheb Bhimrao Ambedkar University, Lucknow, Uttar Pradesh, India.
Abstract:
Multidrug-resistant TB (MDR TB) disease is caused by TB bacteria that are resistant to at least isoniazid and rifampicin, the most effective first-line TB treatment drugs. MDR-TB poses a significant global health challenge due to its resistance to multiple antibiotics. World Health Organization (WHO) and other global health agencies have initiated targeted efforts to control its spread. The recent initiative taken by WHO is ENDTB Universal access to TB prevention and care. However, the eradication of the TB epidemic remains a challenging problem due to the emergence of specialized and modified drug resistance mechanisms. Among these mechanisms, the major facilitator superfamily (MFS) transporters play a crucial role in mediating drug resistance. The Rv0191 efflux transporter protein, a putative member of the MFS, has recently emerged as a potential target for investigating the molecular mechanisms behind the multidrug resistance (MDR) mechanism in Mtb, as it is involved in the efflux of PZA. To investigate the detailed molecular mechanism of Rv0191-mediated drug efflux, two conformations were studied: an outward-open (protonated) conformation for protonation analysis and an inward-open (unprotonated) conformation to examine substrate efflux. Pyrazinamide (PZA), a first-line anti-tuberculosis drug, was selected as the model substrate. Both conformations revealed a central tunnel with a single, distinct binding pocket. The efflux process was explored through a protonation-driven mechanism, highlighting the functional distinctions between the two conformational states. The systems were embedded in a 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphoethanolamine lipid bilayer, and 500 ns of molecular dynamics simulations in triplicate were conducted for the PZA-docked structure. Trajectory-based structural analyses revealed specific interactions between PZA and the binding pocket, accompanied by conformational changes in Rv0191 that MD simulations indicate substrate movement. The observed structural dynamics suggest a plausible efflux pathway, allowing translocation of PZA from the cytoplasmic to the periplasmic side through the central tunnel, thereby suggesting a plausible mechanism of MFS-mediated drug resistance.
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