Efficiency of Antimicrobial Peptides Against Multidrug-Resistant Staphylococcal Pathogens

Abstract

Antibiotics play a vital role in saving millions of lives from fatal infections; however, the inappropriate use of antibiotics has led to the emergence and propagation of drug resistance worldwide. Multidrug-resistant bacteria represent a significant challenge to treating infections due to the limitation of available antibiotics, necessitating the investigation of alternative treatments for combating these superbugs. Under such circumstances, antimicrobial peptides (AMPs), including human-derived AMPs and bacteria-derived AMPs (so-called bacteriocins), are considered potential therapeutic drugs owing to their high efficacy against infectious bacteria and the poor ability of these microorganisms to develop resistance to them. Several staphylococcal species including Staphylococcus aureus, Staphylococcus epidermidis, Staphylococcus haemolyticus, and Staphylococcus saprophyticus are commensal bacteria and known to cause many opportunistic infectious diseases. Methicillin-resistant Staphylococci, especially methicillin-resistant S. aureus (MRSA), are of particular concern among the critical multidrug-resistant infectious Gram-positive pathogens. Within the past decade, studies have reported promising AMPs that are effective against MRSA and other methicillin-resistant Staphylococci. This review discusses the sources and mechanisms of AMPs against staphylococcal species, as well as their potential to become chemotherapies for clinical infections caused by multidrug-resistant staphylococci.

Keywords: MRSA; MRSE; antimicrobial peptides; bacteriocins; human AMPs; staphylococci.

Figure 1

The membrane-disruptive and non-membrane-disruptive antibacterial mechanisms of antimicrobial peptides (AMPs). In the membrane-disruptive mechanisms, three types of interaction can occur between the membrane and the AMPs, including: (i) barrel-stave model: the peptide monomers form a hydrophilic transmembrane channel by arranging parallelly to the phospholipids of the membrane; (ii) carpet model: the peptides solubilize the membrane into micellar structures; and (iii) toroidal model: the lipid moieties fold inward due to the cascade aggregation of peptide monomers, forming a peptide-and-lipid-lined channel.

Figure 2

Amino acid sequences of human antimicrobial peptides (AMPs). The disulfide bonds in α- and β-defensins are indicated by solid lines. The histamine residues in Histatin-1 and -3 are indicated by bold letters.

Figure 3

Amino acid structures of some bacteriocins belonging to different groups.

Figure 4

Amino acid structures of lantibiotic bacteriocins.

Figure 5

Examples of bacteriocin resistance mechanisms in Staphylococcus aureus. I. In the ApsRS system, the sensing of cationic antimicrobial peptides (AMPs) results in the autophosphorylation of ApsS, followed by the phosphorylation of ApsR. The phosphorylated ApsR can bind to the upstream regions of mprF and dltABCD, increasing the expression of these factors. MprF is associated with the addition of lysine to phosphatidylglycerol in the cell membrane, and DltABCD is associated with the addition of alanine to teichoic acids on the cell wall. Amino acid incorporation causes a shift to a weak negative charge on the cell surfaces and makes the cell less sensitive to cationic AMPs. II. In the BraRS (NsaRS)/BraDE system, sensing of nisin A by BraDE results in the autophosphorylation of BraS, followed by the phosphorylation of BraR. The phosphorylated BraR can bind to the upstream region of vraDE, giving rise to the increased expression of an ABC transporter VraDE which expels the AMPs from the cell.

Figure 6

Schematic diagram of the nisin A highly resistant mechanism. I. A point mutation in the promoter region results in the higher expression of braXRS. This leads to the increased induction of vraDE expression by nisin A. II. A point mutation in braS (encoding a sensor protein) causes nisin A-independent phosphorylation of BraS, resulting in increased phosphorylated BraR, which induces a constant expression of vraDE. III. A point mutation in braR (encoding a response regulator) results in nisin A-independent activation of vraDE expression. IV. A point mutation in pmtR encoding a negative regulator PmtR for pmtABCD expression. Mutated PmtR, which lacks the DNA binding ability, results in a constant pmtABCD expression.