Converting a Staphylococcus aureus Toxin into Effective Cyclic Pseudopeptide Antibiotics

Abstract

Staphylococcus aureus produces peptide toxins that it uses to respond to environmental cues. We previously characterized PepA1, a peptide toxin from S. aureus, that induces lytic cell death of both bacterial and host cells. That led us to suggest that PepA1 has an antibacterial activity. Here, we demonstrate that exogenously provided PepA1 has activity against both Gram-positive and Gram-negative bacteria. We also see that PepA1 is significantly hemolytic, thus limiting its use as an antibacterial agent. To overcome these limitations, we converted PepA1 into nonhemolytic derivatives. Our most promising derivative is a cyclic heptapseudopeptide with inconsequential toxicity to human cells, enhanced stability in human sera, and sharp antibacterial activity. Mechanistically, linear and helical PepA1 derivatives form pores at the bacterial and erythrocyte surfaces, while the cyclic peptide induces bacterial envelope reorganization, with insignificant action on the erythrocytes. Our work demonstrates that bacterial toxins might be an attractive starting point for antibacterial drug development.

Structure, Biology, and Therapeutic Application of Toxin–Antitoxin Systems in Pathogenic Bacteria

“…In addition, the toxins have to be effectively delivered to habitats of pathogenic bacteria in the patient’s body without deleterious effects on the human cells or normal commensal organisms. The type I toxin PepA1 from S. aureus is a 30-residue hydrophobic peptide that can cause membrane lysis of both bacterial cells and human erythrocytes [190,191]. This toxin was sequentially and chemically optimized to enhance the antibacterial activity and reduce the hemolytic side effect [191].…”

“…The type I toxin PepA1 from S. aureus is a 30-residue hydrophobic peptide that can cause membrane lysis of both bacterial cells and human erythrocytes [190,191]. This toxin was sequentially and chemically optimized to enhance the antibacterial activity and reduce the hemolytic side effect [191]. The mechanism of action of PepA1 derivatives can be explained by their structural property such as linear, helical, and cyclic conformations [191].…”

“…This toxin was sequentially and chemically optimized to enhance the antibacterial activity and reduce the hemolytic side effect [191]. The mechanism of action of PepA1 derivatives can be explained by their structural property such as linear, helical, and cyclic conformations [191]. A more sophisticated approach would make use of recombinant bacteriophages [192], which deliver the desired toxin gene into pathogenic bacteria.…”

Selectivity Modulation and Structure of α/aza‐β3 Cyclic Antimicrobial Peptides

“…First, we developed strategies to synthesize large series of aza‐β 3 ‐amino acids bearing proteogenic or nonproteogenic side chains suitable for straightforward solid‐phase peptide synthesis . Then, we showed that peptides containing aza‐β 3 ‐amino acids can exert various biological activities and we synthesized highly stable AMP mimics with enhanced antimicrobial activities …”

“…[43][44][45][46] Then, we showedt hat peptides containing azab 3 -amino acids can exert various biological activities [47][48][49] and we synthesized highly stable AMP mimics with enhanced antimicrobial activities. [50][51][52] The large variety of availables ide chains allowed us to design various aza-b 3 -peptidomimetic sequences, while the abiotic moieties confer resistance against proteolytic degradation. Indeed,w hen incorporated into al inear peptide, aza-b 3amino acids are knownt oe nhance the resistance of the pseudopeptide to enzymatic degradation,a nd we showed that cyclic pseudopeptides combine high metabolic stability with a long half-life.…”