Abstract
Considering the emergence of bacterial resistance and low proteolytic stability of antimicrobial peptides (AMPs), herein we developed a series of ultra-short triazine based amphipathic polymers (TZP) that are connected with ethylene diamine linkers instead of protease sensitive amide bond. The most potent oligomers, TZP3 and TZP5 not only displayed potent antibacterial action on various drug-resistant pathogens but also exhibited a strong synergic antibacterial activity in combination with chloramphenicol against multidrug-resistant Pseudomonas aeruginosa (MDRPA). Since most of atopic dermatitis (AD) infections are caused by bacterial colonization, we evaluated the potency of TZP3 and TZP5 on AD in vitro and in vivo. In vitro AD analysis of these two polymers showed significant inhibition against the release of β-hexosaminidase and tumor necrosis factor (TNF-α) from RBL-2H3 cells. In AD-like skin lesions in BALB/c mice model, these two polymers displayed significant potency in suppressing dermal and epidermal thickness, mast cell infiltration and pro-inflammatory cytokines expression. Moreover, these polymers exhibited remarkable efficacy over the allergies caused by the imbalance of Th1/Th2 by regulating total IgE and IgG2a. Finally, the impact of treatment effects of these polymers was examined through analyzing the weights and sizes of spleen and lymph node of AD-induced mice.
Highlights
The rapid emergence of drug-resistant pathogens and the shortage in the discovery of new antibiotics become a major concern in the therapeutic world to treat infectious diseases that remain second leading killer globally causing high morbidity and mortality[1,2,3,4]
TZP3 showed similar potency as melittin against all the tested drug-resistant strains, except for CCARM 3095, where it showed a two-fold better profile of activity compared to melittin. These results suggest that our tested compounds TZP3 and TZP5 could be used as a representative for designing antibiotics that are effective against drug-resistant bacteria
We investigated the synergistic effect of TZP3 and TZP5 in combination with three clinically used antibiotics including, chloramphenicol, ciprofloxacin, and oxacillin that are showing the different mechanism of antimicrobial action against Pseudomonas aeruginosa (MDRPA) and display the resistance with a minimum inhibitory concentration (MIC) range of 512−1024 μM
Summary
The rapid emergence of drug-resistant pathogens and the shortage in the discovery of new antibiotics become a major concern in the therapeutic world to treat infectious diseases that remain second leading killer globally causing high morbidity and mortality[1,2,3,4]. To overcome the drawbacks mentioned above, several strategies have been implemented, including, modification in the peptide sequences using unnatural amino acids or D-amino acids and the development of new peptidomimetics to mimic the properties of AMPs11–16 Even though they show a substantial difference from peptides, the amide functionality remains unchanged, which is highly prone to protease destabilization. We designed and synthesized triazine monomers holding hydrophilic and lipophilic moieties, which were adopted in SPPS for construction of a series of polymers ranging the length from two to five residues These sequence defined polymers were screened against Gram-positive and Gram-negative bacterial strains. As most of atopic dermatitis skin infections involve bacterial colonization, an antibacterial agent with enhanced anti-inflammatory action has been treated for AD18 In this context, TZP-3 and TZP-5 were evaluated for their potential on AD involving both in vitro and in vivo. Weight and size reduction in spleen and lymph nodes of AD-induced mice after treating with TZP3 and TZP5 were analyzed
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