Abstract
The emergence of multi-drug resistant bacteria forces the therapeutic world into a position, where the development of new and alternative kind of antibiotics is highly important. Herein, we report the development of triazine-based amphiphilic small molecular antibacterial agents as mimics of lysine- and arginine-based cationic peptide antibiotics (CPAs). These compounds were screened against a panel of both Gram-positive and Gram-negative bacterial strains. Further, anti-inflammatory evaluation of these compounds led to the identification of four efficient compounds, DG-5, DG-6, DL-5, and DL-6. These compounds displayed significant potency against drug-resistant bacteria, including methicillin-resistant S. aureus (MRSA), multidrug-resistant P. aeruginosa (MDRPA), and vancomycin-resistant E. faecium (VREF). Mechanistic studies, including cytoplasmic membrane depolarization, confocal imaging and flow cytometry suggest that DG-5, DG-6, and DL-5 kill bacteria by targeting bacterial membrane, while DL-6 follows intracellular targeting mechanism. We also demonstrate that these molecules have therapeutic potential by showing the efficiency of DG-5 in preventing the lung inflammation of lipopolysaccharide (LPS)-induced acute lung injury (ALI) mouse model. More interestingly, DL-6 exhibited impressive potency on atopic dermatitis (AD)-like skin lesions in BALB/c mice model by suppressing pro-inflammatory cytokines. Collectively, these results suggest that they can serve a new class of antimicrobial, anti-inflammatory and anti-atopic agents with promising therapeutic potential.
Highlights
Since the discovery of penicillin in the 1920s, a number of antibiotics have been introduced in the market to treat infectious diseases
Though triazine derived antibacterials are reported[24,25,45], the present work advances in terms of highly symmetrical design, enhanced antibacterial and anti-inflammatory effects, and enhanced potency against drug-resistant pathogens
Our findings from this work demonstrate that substituted triazines are suitable for designing potent antibacterial agents due to their symmetric structures holding amphipathicity as in CPAs and easy access to the synthesis of various derivatives, which led to the identification of four lead compounds DG-5, DG-6, DL-5, and DL-6
Summary
Since the discovery of penicillin in the 1920s, a number of antibiotics have been introduced in the market to treat infectious diseases. CPAs have drawn remarkable attention because they are widely found in species ranging from bacteria to mammals and exhibit potent antimicrobial activities[8,9] They exist in both α-helical and β-sheet forms, which exhibit amphiphilic conformations by presenting the cationic groups on one side and hydrophobic groups on the other side of the molecules that result in cationic/hydrophobic segregations[10,11]. Amphiphilic small molecules containing a lipophilic groups and cationic groups exhibiting controlled hemolytic activity are highly imperative for the discovery of new antibiotics and to overcome peptide-associated disadvantages, including proteolytic instability and poor cell permeability[15,16]. Its underlying mechanisms of action was studied using BALB/c model by measuring the ear thickness in mice with AD-like skin lesions and analyzing the histopathological changes including mast cell count and cytokine expression in ear tissue
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
