Influence of Lipophilicity on the Antibacterial Activity of Polymyxin Derivatives and on Their Ability to Act as Potentiators of Rifampicin
| Autor: | Antoinette Wilson, Roy Lester, S. R. Moss, Mona Simonovic, Naomi Divall, Esther Duperchy, Sonia Ganeshwaran, Omar Abdulle, Steven Boakes, Jaspal Singh, Michael J. Dawson, Pamela Brown, Steven J. Stanway, Rivers Dean Andrew |
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| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
chemistry.chemical_classification Chemistry medicine.drug_class Polymyxin 030106 microbiology Potentiator Cyclic peptide Article Amino acid Anti-Bacterial Agents 03 medical and health sciences 030104 developmental biology Infectious Diseases Biochemistry Lipophilicity medicine Polymyxins Rifampin Bacterial outer membrane Cytotoxicity Antibacterial activity |
| Zdroj: | ACS Infect Dis |
| ISSN: | 2373-8227 |
| Popis: | Novel polymyxin derivatives are often classified either as having direct activity against Gram-negative pathogens or as compounds inactive in their own right, which through permeabilization of the outer membrane act as potentiators of other antibiotics. Here, we report the systematic investigation of the influence of lipophilicity on microbiological activity (including against strains with reduced susceptibility to polymyxins), potentiation of rifampicin, and in vitro toxicity within a series of next-generation polymyxin nonapeptides. We demonstrate that the lipophilicity at the N-terminus and amino acids 6 and 7 in the cyclic peptide core is interchangeable and that the activity, ability to potentiate, and cytotoxicity all appear to be primarily driven by overall lipophilicity. Our work also suggests that the characterization of a polymyxin molecule as either a direct acting compound or a potentiator is more of a continuum that is strongly influenced by lipophilicity rather than as a result of fundamentally different modes-of-action. |
| Databáze: | OpenAIRE |
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