Several oligo-acyl-lysyl (OAK)1 analogs were investigated for chemo-sensitization of common pathogenic Gram-negative bacteria (GNB) to rifampin. In-vitro efficacy assays demonstrated that OAK and rifampin were individually incapable to affect bacterial growth efficiently as the minimal inhibitory concentrations (MIC) were generally ≥16 µg/ml, whereas combinations of these drugs revealed to be mutually synergistic since OAKs MIC were reduced by >100 folds in presence of sub-MIC rifampin and inversely, by >5,000 folds. Mechanistic data suggest that chemo-sensitization is likely to result from OAK-mediated outer membrane permabilization, much as proposed for polymyxins, considered gold standard references owing to their high affinity binding to lipopolyscccharides2. Only, having less affinity for these cell-wall constituents, the OAKs can engage in additional membrane damages, thereby achieving superior chemo-sensitization potency. Efficacy was also demonstrated in-vivo as a single dose systemic treatment, using the peritonitis-sepsis model with Klebsiella infected neutropenic mice, where the individual drugs resulted in 10-20% survival of infected mice when the combination therapy achieved 60% survival (P<0.0004). This outcome was achieved without drug formulation; rather, pharmacokinetic considerations have inspired the therapeutic regimen.
Collectively, these findings suggest a potentially useful combination therapy approach for expanding the sensitivity spectrum of GNB to include impermeable antibiotics.
1 Rotem, S. & Mor, A. Antimicrobial peptide mimics for improved therapeutic properties. Biochimica et biophysica acta 1788, 1582-1592 (2009).
2 Storm, D. R., Rosenthal, K. S. & Swanson, P. E. Polymyxin and related peptide antibiotics. Annu Rev Biochem 46, 723-763 (1977).
