Homodimeric Tobramycin Adjuvant Repurposes Novobiocin as an Effective Antibacterial Agent against Gram-Negative Bacteria

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.