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Multidrug-resistant bacteria: overcoming antibiotic permeability barriers of gram-negative bacteria
1Department of Chemistry and Biochemistry, Brigham Young University, Provo, UT 84602, USA. paul_savage@byu.edu
Abstract:
Because of the permeability barrier provided by the outer membrane (OM), gram-negative bacteria are inherently resistant to many hydrophobic antibiotics. This resistance limits the arsenal of antibiotics that are effective in treating gram-negative bacterial infections. Compounding this problem, strains of gram-negative bacteria have emerged that display specific resistance mechanisms for effective antibiotics. As a means of expanding the arsenal of effective antibiotics for gram-negative bacteria, compounds that permeabilize the OM to hydrophobic substances have been developed. These compounds are typically cationic, amphiphilic molecules that can be prepared from peptides or steroids. Effective OM permeabilizers sensitize gram-negative bacteria to hydrophobic antibiotics, including erythromycin, fusidic acid, novobiocin and rifampin. These antibiotics are generally not useful in treating gram-negative bacterial infections because they traverse the OM ineffectively. The use of OM permeabilizers, in combination with hydrophobic antibiotics, may provide additional means of controlling growth of gram-negative bacteria. This review describes classes of permeabilizers, including those derived from peptides, and recently reported examples based on steroids.
Insights
Outer membrane permeability in gram-negative bacteria hinders antibiotic effectiveness. New compounds that permeabilize the outer membrane can restore antibiotic efficacy, offering new strategies against resistant bacterial infections.
Area of Science:
- Microbiology
- Pharmacology
- Drug Discovery
Background:
- Gram-negative bacteria possess an outer membrane (OM) acting as a permeability barrier, conferring inherent resistance to many hydrophobic antibiotics.
- Emergence of specific resistance mechanisms further limits effective antibiotic treatment options for gram-negative infections.
- Hydrophobic antibiotics like erythromycin and rifampin are generally ineffective against gram-negative bacteria due to poor OM penetration.
Purpose of the Study:
- To review compounds that enhance the permeability of the gram-negative bacterial OM to hydrophobic substances.
- To explore strategies for expanding the antibiotic arsenal against challenging gram-negative bacterial infections.
- To discuss the potential of combining OM permeabilizers with existing hydrophobic antibiotics.
Main Methods:
- Review of scientific literature on OM permeabilizers and their mechanisms of action.
- Categorization of permeabilizers based on their chemical origins (peptides, steroids).
- Analysis of studies demonstrating the synergistic effects of OM permeabilizers and hydrophobic antibiotics.
Main Results:
- OM permeabilizers, often cationic and amphiphilic, can sensitize gram-negative bacteria to hydrophobic antibiotics.
- Peptide-derived and steroid-based compounds are key classes of OM permeabilizers.
- Combination therapy with OM permeabilizers and hydrophobic antibiotics shows promise for controlling bacterial growth.
Conclusions:
- OM permeabilizers represent a promising approach to overcome intrinsic gram-negative bacterial resistance.
- The development and application of OM permeabilizers can broaden the utility of established hydrophobic antibiotics.
- Combination strategies involving OM permeabilizers offer a potential new avenue for combating gram-negative bacterial infections.