Synthesis of short cationic antimicrobial peptidomimetics containing arginine analogues

Abstract

Worldwide efforts are underway to develop new antimicrobial agents against bacterial resistance. To identify new compounds with a good antimicrobial profile, we designed and synthesized two series of small cationic antimicrobial peptidomimetics (1-8) containing unusual arginine mimetics (to introduce cationic charges) and several aromatic amino acids (bulky moieties to improve lipophilicity). Both series were screened for in vitro antibacterial activity against a representative panel of Gram-positive (Staphylococcus aureus and Staphylococcus epidermidis) and Gram-negative (Escherichia coli and Klebsiella pneumoniae) bacterial strains, and Candida albicans. The biological screening showed that peptidomimetics containing tryptophan residues are endowed with the best antimicrobial activity against S. aureus and S. epidermidis in respect to the other synthesized derivatives (MIC values range 7.5-50 µg/ml). Moreover, small antimicrobial peptidomimetics derivatives 2 and 5 showed an appreciable activity against the tested Gram-negative bacteria and C. albicans. The most active compounds (1-2 and 5-6) have been tested against Gram-positive established biofilm, too. Results showed that the biofilm inhibitory concentration values of these compounds were never up to 200 µg/ml. The replacement of tryptophan with phenylalanine or tyrosine resulted in considerable loss of the antibacterial action (compounds 3-4 and 7-8) against both Gram-positive and Gram-negative bacterial strains. Furthermore, by evaluating hemolytic activity, the synthesized compounds did not reveal cytotoxic activities, except for compound 5.

Structure–activity relationships of guanylated antimicrobial polymethacrylates

“…This is surprising given the high prevalence of AMPs containing substantial amounts of the amino acid arginine, which bears a pendant guanidine group that is positively charged at the pH typical of buffered mammalian body fluids. Moreover, many studies suggest that high arginine content can be correlated with strong bacterial cell-lytic behavior [9][10][11][12][13] and that arginine-rich AMPs can function as more effective antimicrobials than equivalent lysine-rich peptides [14]. This may be explained by the fact that a guanidine group is capable of forming multidendate bonds with the anionic phosphate headgroups (Fig.…”

Biofilm-Responsive Polymeric Nanoparticles with Self-Adaptive Deep Penetration for In Vivo Photothermal Treatment of Implant Infection

“…In recent years, polymeric materials have been developed as novel antimicrobial agents that mimic antimicrobial peptides. , Cationic polymeric antimicrobials have been explored to inhibit bacteria with minimal possibility to develop resistance. − The positive charge of polymeric antimicrobials is favorable for efficient adhesion with negatively charged bacteria via electrostatic interactions; − however, positively charged nanoparticles are unfavorable in blood circulation, , which inclined to complex with blood components via protein-mediated opsonization, resulting in quick blood clearance and probable side effects. , A charge reversal strategy has been developed to temporarily cage the positive charge of cationic polymers for anticancer drug delivery, while the positively charged native moieties can be reactivated in response to diverse stimuli. , Very recently, it has attracted increasing interest in the treatment of bacterial inhibition. ,, Notably, antimicrobial peptides have broad-spectrum antibacterial ability to treat bacterial infections, containing a high content of arginine and lysine residues, so ammonium and guanidine moieties were speculated be beneficial for the bacterial inhibition in antimicrobial peptides and polymeric antimicrobials. − …”

The Efficacy of the Quorum Sensing Inhibitor FS8 and Tigecycline in Preventing Prosthesis Biofilm in an Animal Model of Staphylococcal Infection

“…To determine the MBC, the MH broth containing FS8 was removed from each well and replaced with antibiotic-free MH broth; the plates were incubated again for 18 h at 37 °C in air. The MBC was taken as the lowest concentration of tigecycline that resulted in no bacterial growth following removal of the drug [10]. In addition, to investigate the effect of FS8 pre-treatment on bacterial antibiotic susceptibility, MIC and MBC were determined after pre-treatment of cells for 30 min with 10 μg FS8 in 10 μL MH broth/well.…”

“…Once formed, biofilms may be up to 1000 times more resistant to antimicrobial agents than planktonic cells alone making them particularly difficult to eliminate [8,9]. Several compounds have been used in many in vitro and in vivo biofilm models [10–14], but none of them significantly eradicate bacterial colonization. Moreover, the widespread use of antibiotics has led to the emergence of multidrug-resistant bacterial strains [15,16].…”