Abstract:
:Low permeability across the outer membrane is a major reason why most antibiotics are ineffective against Gram-negative bacteria. Agents that permeabilize the outer membrane are typically toxic at their effective concentrations. Here, we report the development of a broad-spectrum homodimeric tobramycin adjuvant that is nontoxic and more potent than the gold standard permeabilizing agent, polymyxin B nonapeptide. In pilot studies, the adjuvant confers potent bactericidal activity on novobiocin against Gram-negative bacteria, including carbapenem-resistant and colistin-resistant strains bearing plasmid-borne mcr-1 genes. Resistance development to the combination was significantly reduced, relative to novobiocin alone, and there was no induction of cross-resistance to other antibiotics, including the gyrase-acting fluoroquinolones. Tobramycin homodimer may allow the use of lower doses of novobiocin, overcoming its twin problem of efficacy and toxicity.
journal_name
J Med Chemjournal_title
Journal of medicinal chemistryauthors
Idowu T,Ammeter D,Rossong H,Zhanel GG,Schweizer Fdoi
10.1021/acs.jmedchem.9b00876subject
Has Abstractpub_date
2019-10-24 00:00:00pages
9103-9115issue
20eissn
0022-2623issn
1520-4804journal_volume
62pub_type
杂志文章abstract::Reports of a high-affinity ligand for E-selectin, sialyl di-Lewis(x) (sLe(x)Le(x), 1), motivated us to incorporate modifications to previously reported biphenyl-based inhibitors that would provide additional interactions with the protein. These compounds were assayed for the ability to inhibit the binding of sialyl Le...
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