Abstract
The great clinical significance of biofilm-associated infections and their inherent recalcitrance to antibiotic treatment urgently demand the development of novel antibiofilm strategies. In this regard, antimicrobial peptides (AMPs) are increasingly recognized as a promising template for the development of antibiofilm drugs. Indeed, owing to their main mechanism of action, which relies on the permeabilization of bacterial membranes, AMPs exhibit a strong antimicrobial activity also against multidrug-resistant bacteria and slow-growing or dormant biofilm-forming cells and are less prone to induce resistance compared to current antibiotics. Furthermore, the antimicrobial potency of AMPs can be highly increased by combining them with conventional (antibiotics) as well as unconventional bioactive molecules. Combination treatments appear particularly attractive in the case of biofilms since the heterogeneous nature of these microbial communities requires to target cells in different metabolic states (e.g., actively growing cells, dormant cells) and environmental conditions (e.g., acidic pH, lack of oxygen or nutrients). Therefore, the combination of different bioactive molecules acting against distinct biofilm components has the potential to facilitate biofilm control and/or eradication. The aim of this review is to highlight the most promising combination strategies developed so far to enhance the therapeutic potential of AMPs against bacterial biofilms. The rationale behind and beneficial outcomes of using AMPs in combination with conventional antibiotics, compounds capable of disaggregating the extracellular matrix, inhibitors of signaling pathways involved in biofilm formation (i.e., quorum sensing), and other peptide-based molecules will be presented and discussed.
Highlights
Over the last years, growing efforts have been devoted to the identification of novel therapeutic strategies capable of coping with biofilm-associated infections
Particular attention is focused on combinatorial strategies involving the use of antimicrobial peptides (AMPs) with: (i) conventional antibiotics, (ii) compounds capable of disaggregating the biofilm extracellular matrix or inhibiting its synthesis, (iii) inhibitors of quorum sensing (QS) and/or other signaling pathways implicated in biofilm formation, and (iv) other AMPs and/or peptide-based molecules
Due to its ability to translocate across the outer membrane, it is likely that cathelicidinrelated antimicrobial peptides (CRAMP) functioned as a carrier peptide for the transfer of vancomycin into the periplasm of Gram-negative bacteria (Figure 1A)
Summary
Over the last years, growing efforts have been devoted to the identification of novel therapeutic strategies capable of coping with biofilm-associated infections. The identification of synergistic (peptide-based) combinations has the potential to decrease the effective concentration of the active molecules and to extend their spectrum of action, thereby reducing possible toxic side effects and the spread of resistance, often linked to monotherapy regimens (Walkenhorst, 2016). In addition to these general advantages, the use of combination therapies seems to be indicated in the case of biofilms as their complex architecture requires to target cells in different metabolic states and environmental conditions (Batoni et al, 2016).
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