Antibacterial activity of amphiphilic tobramycin

Abstract

Amphiphilic aminoglycoside antimicrobials are an emerging class of new antibacterial agents with novel modes of action. Previous studies have shown that amphiphilic neomycin-B and kanamycin-A analogs restore potent antibacterial activity against Gram-positive neomycin-B-and kanamycin-A-resistant organisms. In this paper, we investigated the antibacterial properties of a series of amphiphilic tobramycin analogs. We prepared tobramycin-lipid conjugates, as well as tobramycin-peptide triazole conjugates, and studied their antibacterial activities against a panel of Gram-positive and Gram-negative bacterial strains, including isolates obtained from Canadian hospitals. Our results demonstrate that the antibacterial activity of amphiphilic tobramycin is greatly affected by the length and nature of the hydrophobic lipid tail, whereas the nature of the polycationic headgroup or the number of cationic charges appear to be less important. Replacement of the hydrophobic tail by a fluorinated lipid confers good activity against two Pseudomonas strains and reduces hemolytic activity. However, susceptibility studies in the presence of bovine serum albumin indicate that all amphiphilic tobramycin analogs are strongly protein-bound, leading to a typical four-to eight-fold increase in MIC.

Antifungal amphiphilic aminoglycosides

“…These initial observations were expanded in subsequent reports revealing enhanced antibacterial activities with attachment of alkyl and other hydrophobic moieties to neamine, 8,10,13 paromomycin, 7,9,13 and tobramycin. 11,12 These new discoveries with antibacterial amphiphilic aminoglycosides immediately raise questions about their mechanisms of action, and (not surprisingly) interactions with cell surface membranes are implicated. Several observations indicate membrane perturbation as the primary antibacterial action of these compounds and not ribosome interaction to cause protein translation misreading.…”

Engineering Persister-Specific Antibiotics with Synergistic Antimicrobial Functions

“…17,18 Importantly, although AMP killing activity is typically lower than that of aminoglycosides, their membrane activity depends less on the metabolic status of the cell. 19 Previous work has shown that tobramycin can retain good activity after conjugation to lipid tails, 20,21 and there are a few examples of composite molecules with dual antimicrobial effect. 22 However, there is no general methodology for combining two distinct antimicrobial functions into a single molecule without mutual interference.…”

Direct Mitsunobu monoesterification of N-protected tobramycin competes with intramolecular pyrrolidine formation in ester prodrug synthesis

“…The reaction mixture was then concentrated in vacuo and subjected to column chromatography on silica gel (DCM/MeOH 95:2/95:5) to afford compound 3 as a white amorphous solid (19 mg, 33% yield). NH I ), 6.46 (1H, d, J¼6.6 Hz, NH II ), 5.52 (1H, d, J¼3.6 Hz, H 1III ), 5.50 (1H,d,J¼3.7 Hz,H 1I ),4.89 (1H,dd,J¼2.4,11.8 Hz,H 6III ),4.79 (1H,dd,J¼11.8,4.8 Hz,H 6 0 III ),4.67 (1H,ddd,J¼2.4,4.7,7.5 Hz,H 5III ),4.37 (1H,ddd,J¼7.5,7.5,10.2 Hz,H 3III ),4.26 (1H,ddd,J¼4.4,4.4,9. 13 Hz, H 2II eq), 2.60 (1H, ddd, J¼4.5, 4.5, 12 Hz, H 3I eq), 2.52 (2H, t, J¼7.4 Hz, eCOCH 2 , H 2 0 ), 2.23 (1H, m, H 3I ax), 1.96 (1H, m, H 2II ax), 1.77 (2H, tt, J¼7 Hz, H 3 0 ), 1.63e1.53 (5Â s, COC(CH 3 ) 3 ) 1.40e1.33 (br m, H 4 0 -H 11 0 ) 0.96 (m, H 12 0 ). 13 C { 1 H} NMR (100 MHz, pyridine-d 5 , 298K): d 173.6 (COO), 158.0e156.1 (5Â Boc C]O), 99.7 (C 1III , C 1I ), 83.4 (C 6II , C 4II ), 78.8e78.3 (5Â Boc C q ), 75.9 (C 5II ), 73.7 (C 5I ), 72.2 (C 5III ), 71.5(C 2III ), 69.3 (C 4III ), 65.9 (C 4I ), 64.0 (C 6III ), 57.8 (C 3III ), 51.0e50.7 (C 1II , C 3II , C 2I ), 42.0 (C 6I ), 35.9 (C 2II ), 34.6 (C 3I ), 34.3 (C 2 0 ), 32.1 (C 10 0 ), 29.9e29.5 (C 4 0 -C 9 0 ), 28.5 (5Â Boc (CH 3 ) 3 ), 25.3 (C 3 0 ), 23.0 (C 11 0 ), 14.3 (C 12 0 ).…”