TY - JOUR
T1 - Antimicrobial Peptides and Small Molecules Targeting the Cell Membrane of Staphylococcus aureus
AU - Ganesan, Narchonai
AU - Mishra, Biswajit
AU - Felix, Lewis Oscar
AU - Mylonakis, Eleftherios
N1 - Funding Information:
This study was supported by National Institutes of Health Grant P01 AI083214 to E.M. This work was supported by P20GM121344 from the National Institute of General Medical Sciences, which funds the Center for Antimicrobial Resistance and Therapeutic Discovery to B.M.
Publisher Copyright:
Copyright © 2023 American Society for Microbiology. All Rights Reserved.
PY - 2023/6/28
Y1 - 2023/6/28
N2 - 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.
AB - 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.
KW - antimicrobial peptides
KW - biofilm
KW - persister
KW - small molecules
KW - Staphylococcus aureus
KW - Cell Membrane
KW - Humans
KW - Methicillin-Resistant Staphylococcus aureus/genetics
KW - Peptides, Cyclic/therapeutic use
KW - Anti-Bacterial Agents/pharmacology
KW - Anti-Infective Agents
KW - Staphylococcal Infections/drug therapy
KW - Biofilms
KW - Antimicrobial Peptides
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U2 - 10.1128/mmbr.00037-22
DO - 10.1128/mmbr.00037-22
M3 - Review article
C2 - 37129495
AN - SCOPUS:85164210673
SN - 1092-2172
VL - 87
SP - e0003722
JO - Microbiology and Molecular Biology Reviews
JF - Microbiology and Molecular Biology Reviews
IS - 2
ER -