Application of Antimicrobial Peptides of the Innate Immune System in Combination With Conventional Antibiotics—A Novel Way to Combat Antibiotic Resistance?

Abstract

Rapidly growing resistance of pathogenic bacteria to conventional antibiotics leads to inefficiency of traditional approaches of countering infections and determines the urgent need for a search of fundamentally new anti-infective drugs. Antimicrobial peptides (AMPs) of the innate immune system are promising candidates for a role of such novel antibiotics. However, some cytotoxicity of AMPs toward host cells limits their active implementation in medicine and forces attempts to design numerous structural analogs of the peptides with optimized properties. An alternative route for the successful AMPs introduction may be their usage in combination with conventional antibiotics. Synergistic antibacterial effects have been reported for a number of such combinations, however, the molecular mechanisms of the synergy remain poorly understood and little is known whether AMPs cytotoxicy for the host cells increases upon their application with antibiotics. Our study is directed to examination of a combined action of natural AMPs with different structure and mode of action (porcine protegrin 1, caprine bactenecin ChBac3.4, human alpha- and beta-defensins (HNP-1, HNP-4, hBD-2, hBD-3), human cathelicidin LL-37), and egg white lysozyme with varied antibiotic agents (gentamicin, ofloxacin, oxacillin, rifampicin, polymyxin B, silver nanoparticles) toward selected bacteria, including drug-sensitive and drug-resistant strains, as well as toward some mammalian cells (human erythrocytes, PBMC, neutrophils, murine peritoneal macrophages and Ehrlich ascites carcinoma cells). Using “checkerboard titrations” for fractional inhibitory concentration indexes evaluation, it was found that synergy in antibacterial action mainly occurs between highly membrane-active AMPs (e.g., protegrin 1, hBD-3) and antibiotics with intracellular targets (e.g., gentamicin, rifampcin), suggesting bioavailability increase as the main model of such interaction. In some combinations modulation of dynamics of AMP-bacterial membrane interaction in presence of the antibiotic was also shown. Cytotoxic effects of the same combinations toward normal eukaryotic cells were rarely synergistic. The obtained data approve that combined application of antimicrobial peptides with antibiotics or other antimicrobials is a promising strategy for further development of new approach for combating antibiotic-resistant bacteria by usage of AMP-based therapeutics. Revealing the conventional antibiotics that increase the activity of human endogenous AMPs against particular pathogens is also important for cure strategies elaboration.

Antimicrobial Activity of Protein Fraction from Naja ashei Venom against Staphylococcus epidermidis

“…Firstly, the F2 fraction shows synergistic effects with antibiotics (ampicillin and tetracycline). Despite the fact, that tetracycline and ampicillin belong to two different classes of antibiotics and use different mechanisms of action against bacteria, for both antibiotics, a similar effect for antimicrobial peptides was previously described [42][43][44] and for the whole venom of Bothrops moojeni [45]. The antibacterial effect of ampicillin is based on the inhibition of penicillin-binding proteins involved in cell wall synthesis, whereas tetracycline inhibits 30S subunit during protein synthesis [46].…”

“…The antibacterial effect of ampicillin is based on the inhibition of penicillin-binding proteins involved in cell wall synthesis, whereas tetracycline inhibits 30S subunit during protein synthesis [46]. In general, FIC smaller than MIC makes the protein or peptide factor less toxic and the antibiotic more effective at lower concentrations [44,47]. The mechanism of the creation of synergy is explained in many ways.…”

Comparative severity analysis of colitis in C57BL/6 than BALB/c mice: A novel and rapid model of DSS induced colitis

“…The innate immune system initiated host defence against invasive bacterial pathogens, bacterial endotoxin (LPS), and using specific recognition mechanisms. Antimicrobial peptide was one of the main and early host defence response, directly interact with LPS to inhibit the release of inflammatory cytokines and thus induced an anti-inflammatory effect (30, 31). Lipocalin2 (LCN2) was one of such antimicrobial innate immune glycoprotein which played a role in colitis by mitigating gut injury and maintaining iron homeostasis (32, 33).…”

“…To manage this substantial exposure of endotoxin secreted by gram negative bacteria in to serum gut epithelial cells produced a diverse arsenal of antimicrobial proteins that directly killed or inhibited the growth of microorganisms (30, 44). Lipocalin2 was one of such antimicrobial peptide highly expressed in colitis patients, which binds with the ferric-siderophore complex of bacteria to inhibit bacterial growth (45, 46).…”

Cell-Free Protein Synthesis: A Promising Option for Future Drug Development

“…Antimicrobial peptides (AMPs) are another class of defense molecules that have a wide spectrum of targets; for example, bacteria, viruses, fungi, parasites, and cancer. AMPs are evolving as alternatives to antibiotics [152]. Using lyophilized E. coli CF lysates, ten different AMPs have been synthesized successfully and the functionality of Plasmodium falciparum Wheat germ Interaction of PfMSA180 with CD47 was confirmed by erythrocyte binding assay [133].…”