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Therapies Development Targeting AcrAB-TolC System of Enterobacterales

With advancements in therapeutic approaches, such as efflux pump inhibitors, regulatory disruption, and combination therapies, we are hopeful in our ability to overcome antibiotic resistance. At Ace Infectious, we remain dedicated to pushing the boundaries of therapies development and contributing to the global effort to combat the AcrAB-TolC system in Enterobacterales.

Introduction to AcrAB-TolC of Enterobacterales

The AcrAB-TolC system is a vital component of the resistance machinery in Enterobacterales, including well-known pathogens such as Escherichia coli and Klebsiella pneumoniae. This efflux pump system plays a crucial role in expelling a wide range of antimicrobial compounds, leading to reduced efficacy of conventional antibiotics. As the prevalence of multidrug-resistant strains continues to rise, the need for novel therapies targeting the AcrAB-TolC system has become paramount in the battle against antibiotic resistance.

The AcrAB-TolC system common in E. coli and Salmonella.Fig. 1 The AcrAB-TolC system common in E. coli and Salmonella. (Youlden G H, et al., 2021)

Several Approaches Targeting AcrAB-TolC System

Inhibitors of efflux pump components

These inhibitors can work synergistically with existing antibiotics, restoring their effectiveness by preventing their extrusion. Our researchers are actively exploring the design and optimization of EPIs, aiming to overcome the challenges posed by the structural complexity and versatility of the AcrAB-TolC system.

Disruption of regulatory mechanisms

By disrupting the intricate network of transcriptional regulators, it is possible to downregulate the expression of efflux pumps, rendering the bacteria more susceptible to antibiotics. This strategy holds promise for attenuating the multidrug resistance phenotype and increasing the effectiveness of existing therapies.

Combination therapies

Combination therapies, which involve the simultaneous administration of multiple drugs, are being explored to address the challenges posed by the AcrAB-TolC system. By utilizing a combination of antibiotics and efflux pump inhibitors, it is possible to overcome the efflux-mediated resistance mechanisms more effectively.

Our Therapy Development Services

We are committed to advancing the field of therapies development targeting the AcrAB-TolC system of Enterobacterales. We offer a comprehensive range of services, including:

  • Rational drug design. We employ a rational drug design approach to identify and optimize potential inhibitors of the AcrAB-TolC system. Our expertise in structural biology and medicinal chemistry enables us to design compounds with enhanced efficacy and reduced toxicity, accelerating the drug discovery process.
  • High-throughput screening. Our state-of-the-art screening platforms enable us to evaluate large compound libraries to identify potent inhibitors of the AcrAB-TolC system. Through high-throughput screening assays, we can rapidly identify lead compounds that exhibit promising activity against efflux pumps, paving the way for further optimization and development.
  • In vitro and in vivo studies. We conduct comprehensive in vitro and in vivo studies to assess the efficacy and safety of potential therapies targeting the AcrAB-TolC system. These studies encompass antibacterial activity testing, pharmacokinetic evaluations, toxicity assessments, etc.

Future Challenges

  • The high structural variability and adaptability of the AcrAB-TolC system
  • The intricate regulatory networks governing efflux pump expression

The AcrAB-TolC system represents a formidable challenge in the battle against multidrug-resistant Enterobacterales. Contact us to learn how to carry out and advance your development project.

Reference

  1. Youlden G H, et al. Time dependent asymptotic analysis of the gene regulatory network of the AcrAB-TolC efflux pump system in gram-negative bacteria. Journal of Mathematical Biology, 2021, 82: 1-48.
All of our services are intended for preclinical research use only and cannot be used to diagnose, treat or manage patients.
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