Effects of Lysine <i>N</i>-ζ-Methylation in Ultrashort Tetrabasic Lipopeptides (UTBLPs) on the Potentiation of Rifampicin, Novobiocin, and Niclosamide in Gram-Negative Bacteria
Outer membrane (OM) drug impermeability typically associated with a molecular weight above 600 Da and high hydrophobicity prevents accumulation of many antibiotics in Gram-negative bacteria (GNB). Previous studies have shown that ultrashort tetrabasic lipopeptides (UTBLPs) containing multiple lysine...
| Main Authors: | , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2022-03-01
|
| Series: | Antibiotics |
| Subjects: | |
| Online Access: | https://www.mdpi.com/2079-6382/11/3/335 |
| _version_ | 1827650151508869120 |
|---|---|
| author | Linus Schweizer Danyel Ramirez Frank Schweizer |
| author_facet | Linus Schweizer Danyel Ramirez Frank Schweizer |
| author_sort | Linus Schweizer |
| collection | DOAJ |
| description | Outer membrane (OM) drug impermeability typically associated with a molecular weight above 600 Da and high hydrophobicity prevents accumulation of many antibiotics in Gram-negative bacteria (GNB). Previous studies have shown that ultrashort tetrabasic lipopeptides (UTBLPs) containing multiple lysine residues potentiate Gram-positive bacteria (GPB)-selective antibiotics in GNB by enhancing OM permeability. However, there is no available information on how <i>N</i>-substitution at the ζ-position of lysine in UTBLPs affects antibiotic potentiation in GNB. To study these effects, we prepared a series of branched and linear UTBLPs that differ in the degree of <i>N</i>-ζ-methylation and studied their potentiating effects with GPB-selective antibiotics including rifampicin, novobiocin, niclosamide, and chloramphenicol against wild-type and multidrug-resistant GNB isolates. Our results show that increasing <i>N</i>-ζ-methylation reduces or abolishes the potentiating effects of UTBLPs with rifampicin, novobiocin, and niclosamide against GNB. No trend was observed with chloramphenicol that is largely affected by efflux. We were unable to observe a correlation between the strength of the antibiotic potentiating effect to the increase in fluorescence in the 1-<i>N</i>-phenylnaphthylamine (NPN) OM permeability assay suggesting that other factors besides OM permeability of NPN play a role in antibiotic potentiation. In conclusion, our study has elucidated crucial structure–activity relationships for the optimization of polybasic antibiotic potentiators in GNB. |
| first_indexed | 2024-03-09T20:12:22Z |
| format | Article |
| id | doaj.art-25ac085738264e8a95c735bcbcbd445c |
| institution | Directory Open Access Journal |
| issn | 2079-6382 |
| language | English |
| last_indexed | 2024-03-09T20:12:22Z |
| publishDate | 2022-03-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Antibiotics |
| spelling | doaj.art-25ac085738264e8a95c735bcbcbd445c2023-11-24T00:10:51ZengMDPI AGAntibiotics2079-63822022-03-0111333510.3390/antibiotics11030335Effects of Lysine <i>N</i>-ζ-Methylation in Ultrashort Tetrabasic Lipopeptides (UTBLPs) on the Potentiation of Rifampicin, Novobiocin, and Niclosamide in Gram-Negative BacteriaLinus Schweizer0Danyel Ramirez1Frank Schweizer2Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON M5S 1A8, CanadaDepartment of Chemistry, University of Manitoba, Winnipeg, MB R3T 2N2, CanadaDepartment of Chemistry, University of Manitoba, Winnipeg, MB R3T 2N2, CanadaOuter membrane (OM) drug impermeability typically associated with a molecular weight above 600 Da and high hydrophobicity prevents accumulation of many antibiotics in Gram-negative bacteria (GNB). Previous studies have shown that ultrashort tetrabasic lipopeptides (UTBLPs) containing multiple lysine residues potentiate Gram-positive bacteria (GPB)-selective antibiotics in GNB by enhancing OM permeability. However, there is no available information on how <i>N</i>-substitution at the ζ-position of lysine in UTBLPs affects antibiotic potentiation in GNB. To study these effects, we prepared a series of branched and linear UTBLPs that differ in the degree of <i>N</i>-ζ-methylation and studied their potentiating effects with GPB-selective antibiotics including rifampicin, novobiocin, niclosamide, and chloramphenicol against wild-type and multidrug-resistant GNB isolates. Our results show that increasing <i>N</i>-ζ-methylation reduces or abolishes the potentiating effects of UTBLPs with rifampicin, novobiocin, and niclosamide against GNB. No trend was observed with chloramphenicol that is largely affected by efflux. We were unable to observe a correlation between the strength of the antibiotic potentiating effect to the increase in fluorescence in the 1-<i>N</i>-phenylnaphthylamine (NPN) OM permeability assay suggesting that other factors besides OM permeability of NPN play a role in antibiotic potentiation. In conclusion, our study has elucidated crucial structure–activity relationships for the optimization of polybasic antibiotic potentiators in GNB.https://www.mdpi.com/2079-6382/11/3/335outer membrane permeabilizerantibiotic potentiatorantibiotic adjuvantnovobiocinrifampicinniclosamide |
| spellingShingle | Linus Schweizer Danyel Ramirez Frank Schweizer Effects of Lysine <i>N</i>-ζ-Methylation in Ultrashort Tetrabasic Lipopeptides (UTBLPs) on the Potentiation of Rifampicin, Novobiocin, and Niclosamide in Gram-Negative Bacteria Antibiotics outer membrane permeabilizer antibiotic potentiator antibiotic adjuvant novobiocin rifampicin niclosamide |
| title | Effects of Lysine <i>N</i>-ζ-Methylation in Ultrashort Tetrabasic Lipopeptides (UTBLPs) on the Potentiation of Rifampicin, Novobiocin, and Niclosamide in Gram-Negative Bacteria |
| title_full | Effects of Lysine <i>N</i>-ζ-Methylation in Ultrashort Tetrabasic Lipopeptides (UTBLPs) on the Potentiation of Rifampicin, Novobiocin, and Niclosamide in Gram-Negative Bacteria |
| title_fullStr | Effects of Lysine <i>N</i>-ζ-Methylation in Ultrashort Tetrabasic Lipopeptides (UTBLPs) on the Potentiation of Rifampicin, Novobiocin, and Niclosamide in Gram-Negative Bacteria |
| title_full_unstemmed | Effects of Lysine <i>N</i>-ζ-Methylation in Ultrashort Tetrabasic Lipopeptides (UTBLPs) on the Potentiation of Rifampicin, Novobiocin, and Niclosamide in Gram-Negative Bacteria |
| title_short | Effects of Lysine <i>N</i>-ζ-Methylation in Ultrashort Tetrabasic Lipopeptides (UTBLPs) on the Potentiation of Rifampicin, Novobiocin, and Niclosamide in Gram-Negative Bacteria |
| title_sort | effects of lysine i n i ζ methylation in ultrashort tetrabasic lipopeptides utblps on the potentiation of rifampicin novobiocin and niclosamide in gram negative bacteria |
| topic | outer membrane permeabilizer antibiotic potentiator antibiotic adjuvant novobiocin rifampicin niclosamide |
| url | https://www.mdpi.com/2079-6382/11/3/335 |
| work_keys_str_mv | AT linusschweizer effectsoflysineinizmethylationinultrashorttetrabasiclipopeptidesutblpsonthepotentiationofrifampicinnovobiocinandniclosamideingramnegativebacteria AT danyelramirez effectsoflysineinizmethylationinultrashorttetrabasiclipopeptidesutblpsonthepotentiationofrifampicinnovobiocinandniclosamideingramnegativebacteria AT frankschweizer effectsoflysineinizmethylationinultrashorttetrabasiclipopeptidesutblpsonthepotentiationofrifampicinnovobiocinandniclosamideingramnegativebacteria |