Discovery of AcrAB-TolC pump inhibitors: Virtual screening and molecular dynamics simulation approach

Phan, Thien-Vy; Nguyen, Vu-Thuy-Vy; Nguyen, Cao-Hoang-Hao; Vu, Thanh-Thao; Tran, Thanh-Dao; Le, Minh-Tri; Trinh, Dieu-Thuong Thi; Tran, Viet-Hung; Thai, Khac-Minh

doi:10.1080/07391102.2023.2175381

Cited by 5 publications

(5 citation statements)

References 67 publications

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“…Until now, common approaches to the inhibition of efflux pumps comprise the targeting of the efflux pumps' expression, the disruption of the pumps self-assembly process, and the design of new antibiotic molecules that are not recognized by the efflux pumps, as well as new competing substrates to block the pump binding sites [1,7,17,[55][56][57][58]. In spite of the research efforts, only a limited number of inhibitors are currently in the pre-clinical stage and there are no inhibitor drugs for bacterial efflux pumps in clinical use [55].…”

Section: Discussionmentioning

confidence: 99%

Specificity and tunability of efflux pumps: a new role for the proton gradient?

Gerry,

Kirby,

Alexandrov

et al. 2024

Preprint

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Bacterial efflux pumps that transport antibacterial drugs out of the bacterial cells have broad specificity, commonly leading to broad spectrum resistance and limiting treatment strategies for infections. It remains unclear how efflux pumps can maintain this broad spectrum specificity to diverse drug molecules while limiting the efflux of other cytoplasmic content. We investigate the origins of this broad specificity using theoretical models informed by the experimentally determined structural and kinetic properties of efflux pumps. We develop a set of mathematical models describing operation of efflux pumps as a discrete cyclic stochastic process across a network of states characterizing pump conformations and the presence/absence of bound ligands and protons. We find that the pump specificity is determined not solely by the drug affinity to the pump–as is commonly assumed–but it is also directly affected by the periplasmic pH and the transmembrane potential. Therefore, the pump effectiveness in removing a particular drug molecule from the cell can be tuned by modifying the proton concentration gradient and the voltage drop across the membrane. Furthermore, we find that while both the proton concentration gradient across the membrane and the transmembrane potential contribute to the thermodynamic force driving the pump, their effects on the efflux enter not strictly in a combined proton motive force, but rather they have two distinguishable effects on the overall throughput. These results potentially explain the broad specificity of efflux pumps and suggest ways to overcome bacterial resistance, while highlighting unexpected effects of thermodynamic driving forces out of equilibrium.

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Section: Discussionmentioning

confidence: 99%

Specificity and tunability of efflux pumps: a new role for the proton gradient?

Gerry,

Kirby,

Alexandrov

et al. 2024

Preprint

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“…Recent articles have comprehensively reviewed some of the AcrAB−TolC inhibitors, describing their structure-activity relationships, chemical synthesis, mode of action, and in vitro and in vivo activity, as well as their pharmacological properties ( 26 ). Endeavors to develop effective AcrAB−TolC inhibitors are being carried on continuously identifying new molecules, and the development will be facilitated with new approaches such as molecular docking studies and virtual screenings ( 85 - 88 ). Further development of new molecules for clinical uses faces several challenges.…”

Section: Acrab−tolc Inhibitorsmentioning

confidence: 99%

AcrAB-TolC, a major efflux pump in Gram negative bacteria: toward understanding its operation mechanism

Jang

2023

BMB Rep

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Antibiotic resistance (AR) is a silent pandemic that kills millions worldwide. Although the development of new therapeutic agents against antibiotic resistance is in urgent demand, this has presented a great challenge, especially for Gram-negative bacteria that have inherent drug-resistance mediated by impermeable outer membranes and multidrug efflux pumps that actively extrude various drugs from the bacteria. For the last two decades, multidrug efflux pumps, including AcrAB−TolC, the most clinically important efflux pump in Gram-negative bacteria, have drawn great attention as strategic targets for re-sensitizing bacteria to the existing antibiotics. This article aims to provide a concise overview of the AcrAB−TolC operational mechanism, reviewing its architecture and substrate specificity, as well as the recent development of AcrAB−TolC inhibitors.

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“…Our in-house database containing 280 synthetic compounds (ESI† Table S1) was screened through the pharmacophore model RHHa 8 in MOE (Molecular Operating Environment) 2015.10. 9 The 127 compounds that met the query RHHa with sufficient docking scores are presented in Table S2 (ESI†).…”

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confidence: 99%

“…9 The 127 compounds that met the query RHHa with sufficient docking scores are presented in Table S2 (ESI†). Then, the compounds that satisfied the pharmacophore query were prepared for structural analysis by Sybyl-X 2.0 10,11 and subjected to molecular docking with a focus on the binding site of the AcrB's distal pocket 8,12 using LeadIT 2.0.2 software. 13 The results showed that 56 compounds had docking scores less than −20 kJ mol −1 .…”

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confidence: 99%