Synergism between the Synthetic Antibacterial and Antibiofilm Peptide (SAAP)-148 and Halicin

Abstract

Recently, using a deep learning approach, the novel antibiotic halicin was discovered. We compared the antibacterial activities of two novel bactericidal antimicrobial agents, i.e., the synthetic antibacterial and antibiofilm peptide (SAAP)-148 with this antibiotic halicin. Results revealed that SAAP-148 was more effective than halicin in killing planktonic bacteria of antimicrobial-resistant (AMR) Escherichia coli, Acinetobacter baumannii and Staphylococcus aureus, especially in biologically relevant media, such as plasma and urine, and in 3D human infection models. Surprisingly, SAAP-148 and halicin were equally effective against these bacteria residing in immature and mature biofilms. As their modes of action differ, potential favorable interactions between SAAP-148 and halicin were investigated. For some specific strains of AMR E. coli and S. aureus synergism between these agents was observed, whereas for other strains, additive interactions were noted. These favorable interactions were confirmed for AMR E. coli in a 3D human bladder infection model and AMR S. aureus in a 3D human epidermal infection model. Together, combinations of these two novel antimicrobial agents hold promise as an innovative treatment for infections not effectively treatable with current antibiotics.

Encapsulation of SAAP-148 in Octenyl Succinic Anhydride-Modified Hyaluronic Acid Nanogels for Treatment of Skin Wound Infections

“…Indeed, the improved safety of SAAP-148-loaded nanogels compared to SAAP-148 is most pronounced (2.2–3.6-fold) at 4 h exposure but is still observed at 24 h (1.5–2.9-fold), and can be related to the sustained release of SAAP-148 (22–39% at 4 h; 30–41% at 24 h). Notably, the enhanced safety was also proven in a 3D human epidermal model that is more resistant to cytotoxic activities of SAAP-148 [ 29 ].…”

“…Sodium bicarbonate (NaHCO 3 ), sodium hydroxide (NaOH), calcium chloride (CaCl 2 ) and human serum were obtained from Merck (Darmstadt, Germany). SAAP-148 was synthesized using standard Fmoc chemistry, purified to >95% as described previously [ 29 ], and stored lyophilized until use. 6-Carboxytetramethylrhodamine (6-TAMRA)-labeled SAAP-148 (acetyl-LK(6-TAMRA)RVWKRVFKLLKRYWRQLKKPVR-amide) with a purity of 96.9% was purchased from Pepscan (Lelystad the Netherlands).…”

“…Human skin equivalents (HSEs) were cultured over 14 days using Ker-CT cells as previously described in detail [ 29 ]. At least two days before infection, their culture medium was replaced for culture medium without antibiotics.…”

The Mechanism of Action of SAAP-148 Antimicrobial Peptide as Studied with NMR and Molecular Dynamics Simulations

“…The antimicrobial activity of SAAP-148 has been explained by its ability to interact and destabilize the bacterial membrane. This is reflected by the peptide’s ability to disrupt liposomes containing bacterial phospholipids [ 31 , 33 ] and potentiate the activity of other antibiotics [ 12 ]. In this work, we have elucidated its mechanism of action at the molecular level of detail.…”

“…In contrast to standard antibiotics, many AMPs are able to quickly permeate cell membranes causing irreversible damage [ 7 , 10 , 11 ]. For this reason, they can be used in synergy with antibiotics to grant intracellular access to the latter, thus overcoming resistance based on reduced permeabilization of the bacterial membrane [ 12 , 13 ]. Some AMPs are able to bypass the bacterial membrane without damaging it and exert their antimicrobial action intracellularly [ 7 , 10 , 11 , 14 , 15 , 16 , 17 , 18 ].…”