Antibacterial Peptides Resistance in Staphylococcus aureus: Various Mechanisms and the Association with Pathogenicity

Abstract

Staphylococcus aureus is a bacterium that mainly colonizes the nasal cavity and skin. To colonize the host, it is necessary for S. aureus to resist many antibacterial factors derived from human and commensal bacteria. Among them are the bacteria-derived antimicrobial peptides (AMPs) called bacteriocins. It was reported that some two-component systems (TCSs), which are signal transduction systems specific to bacteria, are involved in the resistance to several bacteriocins in S. aureus. However, the TCS-mediated resistance is limited to relatively low concentrations of bacteriocins, while high concentrations of bacteriocins still exhibit antibacterial activity against S. aureus. To determine whether we could obtain highly bacteriocin-resistant mutants, we tried to isolate highly nisin A-resistant mutants by exposing the cells to sub-minimum inhibitory concentrations (MICs) of nisin A. Nisin A is one of the bacteriocins produced by Lactococcus lactis and is utilized as a food preservative worldwide. Finally, we obtained highly nisin A-resistant mutants with mutations in one TCS, BraRS, and in PmtR, which is involved in the expression of pmtABCD. Notably, some highly resistant strains also showed increased pathogenicity. Based on our findings, this review provides up-to-date information on the role of TCSs in the susceptibility to antibacterial peptides. Additionally, the mechanism for high antimicrobial peptides resistance and its association with pathogenicity in S. aureus is elucidated.

Antimicrobial and anti-biofilm activity of Polygonum chinense L.aqueous extract against Staphylococcus aureus

“…S. aureus , a gram-positive bacterium, can cause variety of infections ranging from minor skin and soft tissue infections such as impetigo, folliculitis, and cutaneous abscesses to life-threatening diseases such as sepsis, infective endocarditis or toxic shock syndrome respiratory, tract and bloodstream infections 2 , 3 . Besides, S. aureus can produce a variety of toxins including enterotoxins related to food poisoning, toxic shock syndrome toxin, hemolysin, leukocidin and exfoliative toxins, which generate various diseases ranging from skin infections to systemic life-threatening diseases 4 , 5 . During the past decade, there has been an increasing awareness that S. aureus biofilms are a major cause for concern in multiple infections 6 .…”

Targeting the Holy Triangle of Quorum Sensing, Biofilm Formation, and Antibiotic Resistance in Pathogenic Bacteria

“…Agr also represses the expression of apsRS which confers resistance to antimicrobial peptides such as human β-defensin-3, LL37, and bacteriocins (nisin A, nukacin ISK-1) [380]. ApsR regulates the dlt operon that adds alanine to teichoic acid in the cell wall and mprF (fmtC), which adds lysine to phosphatidylglycerol in cell membranes [381][382][383].…”

“…This leads to a reduced negative charge of the bacterial surface, and a consequently reduced binding of the positively charged antimicrobial peptides [381][382][383]. Since Agr expression is low during the early phase of bacterial growth, while high in the stationary phase, the susceptibility to antimicrobial peptides changes during cell growth with low susceptibility during the exponential phase and high susceptibility in the stationary phase [380,384].…”

Efficiency of Antimicrobial Peptides Against Multidrug-Resistant Staphylococcal Pathogens

“…It was questionable whether highly resistance could evolve if exposed to a high concentration of nisin A. After several experimental trials, finally, some research groups were able to obtain highly nisin A-resistant S. aureus strains with mutations in BraRS, or PmtR when exposing S. aureus to sub-MICs of nisin A ( Blake et al, 2011 ; Arii et al, 2019 ; Kawada-Matsuo et al, 2020 , 2021 ). Arii et al (2019) isolated several nisin A highly resistant S. aureus strains by exposing sub-MIC of nisin A three times and obtained two types of the mutants, with mutations in braRS or pmtR ( Figure 6 ).…”

“…The braS mutation was found in the histidine kinase region, suggesting that the mutated BraS is autophosphorylated without the stimulation of nisin A. Blake et al also reported the point mutation of NsaS (BraS) in nisin-resistant S. aureus strains. Another nisin A highly resistant S. aureus mutant was isolated by the mutation of PmtR with the increased expression of PmtA-D, an ABC transporter, involved in the susceptibility to nisin A and beta-defensin ( Kawada-Matsuo et al, 2020 , 2021 ). Since PmtR was a negative regulator for PmtA-D expression, the mutated PmtR could not bind to the upstream region of pmtA-D .…”