Biofilm infections between Scylla and Charybdis: interplay of host antimicrobial peptides and antibiotics

Abstract

PurposeThe aim of this study is to improve the anti-biofilm activity of antibiotics. We hypothesized that the antimicrobial peptide (AMP) complex of the host’s immune system can be used for this purpose and examined the assumption on model biofilms.MethodsFLIP7, the AMP complex of the blowfly Calliphora vicina containing a combination of defensins, cecropins, diptericins and proline-rich peptides was isolated from the hemolymph of bacteria-challenged maggots. The complex interaction with antibiotics of various classes was studied in biofilm and planktonic cultures of Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa, Klebsiella pneumoniae and Acinetobacter baumannii by the checkerboard method using trimethyl tetrazolium chloride cell viability and crystal violet biofilm eradication assays supplemented with microscopic analysis.ResultsWe found that FLIP7 demonstrated: high synergy (fractional inhibitory concentration index <0.25) with meropenem, amikacin, kanamycin, ampicillin, vancomycin and cefotaxime; synergy with clindamycin, erythromycin and chloramphenicol; additive interaction with oxacillin, tetracycline, ciprofloxacin and gentamicin; and no interaction with polymyxin B. The interaction in planktonic cell models was significantly weaker than in biofilms of the same strains. The analysis of the dose–effect curves pointed to persister cells as a likely target of FLIP7 synergistic effect. The biofilm eradication assay showed that the effect also caused total destruction of S. aureus and E. coli biofilm materials. The effect allowed reducing the effective anti-biofilm concentration of the antibiotic to a level well below the one clinically achievable (2–3 orders of magnitude in the case of meropenem, ampicillin, cefotaxime and oxacillin).ConclusionFLIP7 is a highly efficient host antimicrobial system helping antibiotics to overcome biofilm barriers through persisters’ sensitization and biofilm material destruction. It is promising for the treatment of biofilm infections as an adjuvant of various small-molecule antibiotics.

Caprine Bactenecins as Promising Tools for Developing New Antimicrobial and Antitumor Drugs

“…Unlike many conventional antibiotics, AMPs are capable of acting on metabolically inactive bacteria, since a main target of their action is bacterial membranes; this could be successfully exploited for the elimination of persister cells in combination with conventional drugs, which has been demonstrated by the synergistic interaction of the latter with AMPs against biofilms (Pletzer and Hancock, 2016;Chernysh et al, 2018). It was shown that various AMPs on their own not only eliminate planktonic bacteria, but also weaken the primary adhesion of bacterial cells to the surface, and within the established biofilms can impair the interaction of the elements of extracellular matrix and embedded bacterial cells.…”

Sarconesin: Sarconesiopsis magellanica Blowfly Larval Excretions and Secretions With Antibacterial Properties

“…In another study, AMPs extracted from C. vicina larval haemolymph were applied in environments extremely contaminated by germs forming biofilms (under in situ and in vitro conditions), exhibiting strong destructive activity of the matrix and of bacteria adhered to it, these bacteria were resistant to conventional antibiotics, such as Escherichia coli, Staphylococcus aureus , and Acinetobacter baumannii ( Gordya et al, 2017 ). Likewise, this AMP complex containing a combination of defensins, cecropins, diptericins and proline-rich peptides, and interacting synergistically with antibiotics of various classes, produced a much stronger action on the bacterial strains ( Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa, Klebsiella pneumoniae , and Acinetobacter baumannii ) and the biofilm materials, when compared with the antibacterial effect on the same strains in a model of planktonic cultures ( Chernysh et al, 2018 ).…”

The Synergistic Effect of Mud Crab Antimicrobial Peptides Sphistin and Sph12−38 With Antibiotics Azithromycin and Rifampicin Enhances Bactericidal Activity Against Pseudomonas Aeruginosa

“…As reported in previous studies, in general, aerobic Gram-negative (G-) bacteria are resistant to clindamycin, but clindamycin is effective against the Gram-positive (G+) bacteria, such as S. aureus, Streptococcus pyogenes, S. pneumoniae, and Streptococcus viridans. The synergistic effect of clindamycin combined with AMPs has been reported previously (Spizek et al, 2004;Nguschwemlein et al, 2014;Chernysh et al, 2018). For the G+ bacteria, when clindamycin was used in combination with the AMPs cyclooctapeptides (CPs, including CPs 1-3, 5-7, 10, 11) against S. aureus, all combinations showed partial synergistic effects (0.5 ≤ FICI < 1) (Nguschwemlein et al, 2014).…”

“…For the G+ bacteria, when clindamycin was used in combination with the AMPs cyclooctapeptides (CPs, including CPs 1-3, 5-7, 10, 11) against S. aureus, all combinations showed partial synergistic effects (0.5 ≤ FICI < 1) (Nguschwemlein et al, 2014). When clindamycin was used in combination with FLIP7, the AMP complex from the blowfly Calliphora vicina contains a combination of defensins, cecropins, diptericins, and proline-rich peptides against S. aureus, showing a synergistic effect (Chernysh et al, 2018). To FIGURE 6 | Effect of Sph 12−38 in combination with rifampin and azithromycin, respectively, on wound healing in vivo.…”