Development of Outer Membrane Permeabilizers
Most of the available antibiotics act at the intracellular level. In contrast, certain bacteria have a protective layer represented by an outer membrane that affects bacterial susceptibility to antibiotics. As a result, some emerging resistant strains often have outer membrane modifications that limit the entry of small molecules such as antibiotics. To better improve antibiotic uptake, Ace Therapeutics provides research services in the development of novel antibiotics designing and using outer membrane permeabilizer compounds that can facilitate antibiotic diffusion and increase their intracellular concentration.
Target the Bacterial Cell Permeability
Some antibiotics have limited effectiveness in treating infections caused by Gram-negative bacteria, mainly due to their particularly complex membrane structure. The use of permeabilizers has been shown to be a good way to improve antibiotic uptake. These compounds are usually cationic and amphiphilic, or chelating agents that make the outer layer of the outer membrane unstable. As a result, the outer membrane becomes more permeable, thus promoting drug uptake. For example, mucilage, aminoglycosides, cationic peptides, cationic bile acid derivatives, and polyamines can act as membrane permeabilizing agents.
Fig. 1 Outer membrane permeabilizers as antibiotic adjuvants. (Wright G D, 2016)
Development Services of Outer Membrane Permeabilizers
In order to penetrate into bacteria, antibiotics follow two different pathways. Hydrophobic compounds diffuse through the lipid bilayer. Hydrophilic molecules diffuse through the bacterial pore proteins. Therefore, we can offer the development of antibiotic adjuvants mainly targeting the alteration of pore proteins and membrane channels. All of these are used in combination with antibiotics to control drug-resistant strains.
For lipid-mediated antibiotic resistance
Strains expressing the outer membrane lipid layer are intrinsically resistant to hydrophobic antibiotics and other compounds. For some hydrophobic antibiotics, such as aminoglycosides, macrolides, rifamycin, cationic peptides, etc., that penetrate the lipid layer of the outer membrane to enter the cell interior, we offer the development of molecules with permeabilizing effects such as polymyxins, based on a competitive mechanism that leads to destabilization of the lipid layer to allow the antibiotic to penetrate the inner membrane, and thus act as an antibacterial agent.
For porin-mediated antibiotic resistance
Porin is permeable to β-lactam antibiotics. For some strains that acquire antibiotic resistance through loss or functional changes of porin, such as Escherichia coli, Pseudomonas aeruginosa, Neisseria gonorrhoeae, Enterobacter aerogenes and Klebsiella pneumoniae, we help you better understand the function of general diffusion porin and design and develop penetrators against porin shutdown or inactivation that will allow antibiotics to reuse the pathway under different conditions of penetration efficiency.
Our Service Applications
Our services consist in the development of membrane permeabilizers to weaken the outer membrane and increase the permeability of bacterial cells to antibiotics in a non-specific manner.
- To disrupt the lipid portion of the cell membrane to promote membrane permeability
- To further enhance the antibacterial activity of antibiotics interacting with intracellular targets
- Provide further strategies to treat drug-resistant bacterial infections in combination with antibiotics
The increase in antibiotic resistance to superbugs is alarming. There is a need to find new ways to combat microbial resistance. Antibiotic adjuvant synergistic antibiotic combinations will likely be a strategy to combat the problems of virulence and resistance development. We focus on the development of antibiotic adjuvants. Please contact us if you need supports.
References
- Wright G D. Antibiotic adjuvants: rescuing antibiotics from resistance. Trends in microbiology, 2016, 24(11): 862-871.
- Delcour A H. Outer membrane permeability and antibiotic resistance. Biochim Biophys Acta, 2009, 1794(5): 808-16.