Combination Strategies to Enhance the Efficacy of Antimicrobial Peptides against Bacterial Biofilms

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.

Keywords: antibiofilm strategies; antimicrobial peptides; bacterial biofilms; combination therapies; synergistic interactions.

FIGURE 1

Possible mechanisms of the synergistic activity of AMP-based combinations against bacterial biofilms. AMPs can potentiate the antibiofilm effect of conventional antibiotic by: (A) extending antibiotic spectrum of action; (B) promoting antibiotic intracellular uptake through membrane destabilization; (C) interfering with signaling molecules involved in biofilm formation. Compounds able to target the biofilm EPS can potentiate AMP activity by: (D) inhibiting matrix production in forming biofilms; (E) causing matrix disaggregation in preformed biofilms. (F) QSIs can facilitate the killing of early surface-colonizing bacteria by AMPs by interfering with signaling molecules implicated in biofilm formation. (G) AMPs may synergize with other AMPs with mechanisms still largely unknown. MI, matrix inhibitor; QSI, quorum sensing inhibitor. Dashed lines indicate killing of bacteria or inhibition/disaggregation of biofilm matrix.