Development of Efflux Pump Inhibitors
Active efflux is a mechanism by which bacteria develop resistance to a specific antibiotic or multiple antibiotics. In this context, the use of efflux pump inhibitors (EPIs) appears to be a promising strategy for overcoming multidrug resistance. Efflux pump inhibition can restore the susceptibility of resistant strains to antibiotics and limit the emergence of new resistant mutants.
Fig. 1 Chemical structure of several EPIs. (Mhapankar N, et al., 2022)
Inhibition of efflux provides a powerful strategy to enhance antibiotic activity. Ace Therapeutics provides solutions for restoring bacterial susceptibility through efflux pump inhibitor molecules designed to improve the entry of antibiotics into bacterial cells and prevent their excretion.
Antibiotic Efflux Systems
Bacterial pathogens are constantly squeezing antibiotics out of their cells through the efflux pump, thus developing resistance. Associated bacteria with exocytosis-mediated resistance can overexpress chromosomally encoded exocytosis pumps with antibiotic specificity. However, they usually lack substrate specificity and can efflux a variety of molecules from the cell, resulting in active efflux of multiple antibiotics. The more common antibiotic efflux systems are the major facilitator superfamily (MFS) and the triple RND system found in many gram-negative bacteria. These systems are usually broadly specific.
Development Services of Efflux Pump Inhibitors
For the efflux pump mechanism, we offer different targeting strategies for the development of efflux pump inhibitors. These specifically include,
- To inhibit the expression of genes encoding these pumps
- To prevent assembly of pump components at the membrane level
- To block the membrane exit pipeline
- To deplete the energy required for the operation of these pumps
In addition to the targeting strategy, our development for efflux pump inhibitors takes into account the type of pathogenic bacteria you need to target, the type of efflux pump chosen and the ultimate antibiotic enhancement. The following conditions can be met.
- The inhibitor is specific for the bacterial target and ideally does not have any pharmacological activity against eukaryotic cells.
- It can reach therapeutically effective concentrations and can reach the target of action in vivo.
- The inhibitor does not contain antimicrobial activity to reduce the likelihood of resistance mechanisms.
- It has an acceptable pharmacokinetic profile and a non-toxic profile.
Key Development Points
There are no efflux pump inhibitors for use in humans or animals to treat bacterial infections. There are some research difficulties faced in this research area. We address this by providing the main points.
- One of the main points is the study of various physiological functions targeting the efflux pump, in order to avoid blockage causing other unintended toxicity.
- Another research point is the search for compounds that specifically inhibit pumps that operate only in prokaryotic cells. We can perform extensive studies to identify substrates and inhibitors of these pumps.
Efflux pump inhibitors can be used as broad-spectrum adjuvants, which have potential value in inhibiting resistance. Their toxicity issues hinder their use in clinical settings. We believe that this approach is reasonable and deserves more attention. You can contact us if you are interested in this area of research.
References
- Mhapankar N, et al. Deciphering the Role of β-Lactamase Inhibitors, Membrane Permeabilizers and Efflux Pump Inhibitors as Emerging Targets in Antibiotic Resistance. Indian J Microbiol, 2022, 62, 524–530.
- Hana D, et al. Antibiotic Adjuvants: Make Antibiotics Great Again. Journal of Medicinal Chemistry, 2019, 62 (19), 8665-8681.