Antimicrobial Peptides and Small Molecules Targeting the Cell Membrane of Staphylococcus aureus

Abstract

Clinical management of Staphylococcus aureus infections presents a challenge due to the high incidence, considerable virulence, and emergence of drug resistance mechanisms. The treatment of drug-resistant strains, such as methicillin-resistant S. aureus (MRSA), is further complicated by the development of tolerance and persistence to antimicrobial agents in clinical use. To address these challenges, membrane disruptors, that are not generally considered during drug discovery for agents against S. aureus, should be explored. The cell membrane protects S. aureus from external stresses and antimicrobial agents, but membrane-targeting antimicrobial agents are probably less likely to promote bacterial resistance. Nontypical linear cationic antimicrobial peptides (AMPs), highly modified AMPs such as daptomycin (lipopeptide), bacitracin (cyclic peptide), and gramicidin S (cyclic peptide), are currently in clinical use. Recent studies have demonstrated that AMPs and small molecules can penetrate the cell membrane of S. aureus, inhibit phospholipid biosynthesis, or block the passage of solutes between the periplasm and the exterior of the cell. In addition to their primary mechanism of action (MOA) that targets the bacterial membrane, AMPs and small molecules may also impact bacteria through secondary mechanisms such as targeting the biofilm, and downregulating virulence genes of S. aureus. In this review, we discuss the current state of research into cell membrane-targeting AMPs and small molecules and their potential mechanisms of action against drug-resistant physiological forms of S. aureus, including persister cells and biofilms.

Keywords: Staphylococcus aureus; antimicrobial peptides; biofilm; persister; small molecules.

FIG 1

S. aureus infection model of relapsing biofilms. Figure adapted based on Conlon et al. (216) and Lister et al. (217).

FIG 2

Examples for different types of AMPs based on their structure. (a) Aurein 2.5 (PDB ID: 6GS9); (b) Magainin 2 (PDB ID: 2MAG); (c) Melittin (PDB ID: 2MLT); (d) LL-37 (PDB ID: 2K6O); (e) Lactoferricin B (PDB ID: 1LFC); (f) Human neutrophil peptide-1 (PDB ID: 3GNY); (g) Gomesin (PDB ID: 1KFP); (h) Protegrin 1 (PDB ID: 1PG1); (i) Human β-defensin 1 (PDB ID: 1E4S); (j) Thrombocidin-1 (PDB ID: 1NAP); (k) CXCL10 (PDB ID: 1O80); (l) Actinomycesin (PDB ID: 2RU0); (m) Pyrrhocoricin (PDB ID: 5HD1); and (n) Tridecaptin A1 (PDB ID: 2N5Y). All the images were obtained from the RCSB Protein Data Bank.

FIG 3

Replacing charged (lysine) or low hydrophobic amino acids (glycine) with high hydrophobic amino acids (tryptophane or leucine) enhances the antistaphylococcal activity of Cecropin-4-derived AMPs. The figure is adapted from Peng et al. (70).

FIG 4

Distribution of amino acid residues in α-helical AMPs (determined from the antimicrobial peptide database). Each amino acid is denoted with a single letter: hydrophobic (I, V, L, F, C, M, A, W, G, P), neutral (T, S, Y, N, Q), and charged residues (E, D, H, K, R). (A) Broad spectrum membrane activity. (B) S. aureus-specific membrane activity.

FIG 5

Changing the secondary amine in a series of dialkyl cationic amphiphiles by adding two identical-length lipophilic alkyl chains and one nonpeptidic amide bond to improve the membrane-targeting efficacy against S. aureus. The figure is adapted from Zhang et al. (84).

FIG 6

Mechanism of action of small molecules and AMPs on S. aureus membrane describing barrel-stave model, toroidal pore model, and carpet model. Figure adapted based on Brogden et al. (63).

FIG 7

(A) Sinking raft model. This model illustrates how peptide trimers are inserted and translocated across the lipid bilayer. In the cross sections of ɑ-helical peptides, the darker half-circles represent hydrophobic faces, and the lighter half-circles represent polar faces. The polar angle of δ-lysin is 180°. In step 1, the peptide forms a trimer on the phospholipid surface of the outer membrane. During step 2, the peptide sinks into the outer leaflet of the bilayer. In steps 3 and 4, a cavity is formed, which is the most unstable intermediate state. Finally, in step 5, translocation is completed symmetrically, and the trimer emerges on the inner membrane. The figure was based on the sinking raft model of δ-lysin (120, 218) (B) The “leaky slit” model is used to explain the membrane-damaging action of AMPs such as Plantaricin A (121).

FIG 8

The complex cell wall structure of S. aureus is composed of a thick peptidoglycan layer, lipoteichoic acid, surface protein, and membrane protein. Figure adapted based on Epand et al. (219).