Affiliation:
1. Malaria Research Laboratory, International Centre for Genetic Engineering and Biotechnology, Aruna Asaf Ali Road, New Delhi 110067, India
2. Department of Biosciences, Jamia Millia Islamia, Jamia Nagar, New Delhi 110025, India
Abstract
ABSTRACT
By choosing membranes as targets of action, antibacterial peptides offer the promise of providing antibiotics to which bacteria would not become resistant. However, there is a need to increase their potency against bacteria along with achieving a reduction in toxicity to host cells. Here, we report that three
de novo
-designed antibacterial peptides (ΔFm, ΔFmscr, and Ud) with poor to moderate antibacterial potencies and kill kinetics improved significantly in all of these aspects when synergized with rifampin and kanamycin against
Escherichia
coli
. (ΔFm and ΔFmscr [a scrambled-sequence version of ΔFm] are isomeric, monomeric decapeptides containing the nonproteinogenic amino acid α,β-didehydrophenylalanine [ΔF] in their sequences. Ud is a lysine-branched dimeric peptide containing the helicogenic amino acid α-aminoisobutyric acid [Aib].) In synergy with rifampin, the MIC of ΔFmscr showed a 34-fold decrease (67.9 μg/ml alone, compared to 2 μg/ml in combination). A 20-fold improvement in the minimum bactericidal concentration of Ud was observed when the peptide was used in combination with rifampin (369.9 μg/ml alone, compared to 18.5 μg/ml in combination). Synergy with kanamycin resulted in an enhancement in kill kinetics for ΔFmscr (no killing until 60 min for ΔFmscr alone, versus 50% and 90% killing within 20 min and 60 min, respectively, in combination with kanamycin). Combination of the dendrimeric peptide ΔFq (a K-K2 dendrimer for which the sequence of ΔFm constitutes each of the four branches) (MIC, 21.3 μg/ml) with kanamycin (MIC, 2.1 μg/ml) not only lowered the MIC of each by 4-fold but also improved the therapeutic potential of this highly hemolytic (37% hemolysis alone, compared to 4% hemolysis in combination) and cytotoxic (70% toxicity at 10× MIC alone, versus 30% toxicity in combination) peptide. Thus, synergy between peptide and nonpeptide antibiotics has the potential to enhance the potency and target selectivity of antibacterial peptides, providing regimens which are more potent, faster acting, and safer for clinical use.
Publisher
American Society for Microbiology
Subject
Infectious Diseases,Pharmacology (medical),Pharmacology
Cited by
62 articles.
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