Self-Deliverable Peptide-Mediated and Reactive-Oxygen-Species-Amplified Therapeutic Nanoplatform for Highly Effective Bacterial Inhibition

Abstract

An "antibiotic-free strategy" provides a viable option to address bacterial infections, especially for the "superbug" challenge. However, the undesirable antibacterial activity of antibiotic-free agents hinders their practical applications. In this study, we developed a combination antibacterial strategy of coupling peptide-drug therapy with chemodynamic therapy (CDT) to achieve the effective bacterial inhibition. An amphiphilic oligopeptide (LAOOH-OPA) containing a therapeutic unit of D (KLAK) 2 peptide and a hydrophobic linoleic acid hydroperoxide (LAHP) was designed. The positively charged D (KLAK) 2 peptide with an α-helical conformation enabled rapid binding with microbial cells via electrostatic interaction and subsequent membrane insertion to deactivate the bacterial membrane. When triggered by Fe 2+ , moreover, LAHP could generate singlet oxygen ( 1 O 2 ) to elicit lipid bilayer leakage for enhanced bacteria inhibition. In vitro assays demonstrated that the combination strategy possessed excellent antimicrobial activity not only merely toward susceptible strains (Gram-positive Staphylococcus aureus and Gram-negative Escherichia coli) but also toward methicillinresistant Staphylococcus aureus (MRSA). On the mouse skin abscess model induced by S. aureus, self-assembled LAOOH-OPA exhibited a more significant bacteria reduction (1.4 log 10 reduction) in the bioburden compared to that of the standard vancomycin (0.9 log 10 reduction) without apparent systemic side effects. This combination antibacterial strategy shows great potential for effective bacterial inhibition.

Bactericidal and biofilm eradication efficacy of a fluorinated benzimidazole derivative, TFBZ, against methicillin-resistant Staphylococcus aureus

“…Subsequently, samples were washed with PBS twice and submerged in a 2.5% glutaraldehyde solution for fixation overnight. After gradual dehydration with gradient ethanol (30%, 50%, 70%, 80%, 90%, and 100%) for 10 min each, the biofilms were freeze-dried and sputter-coated with gold ( Huang et al, 2022 ). Finally, the morphology of specimens was imaged under a scanning electron microscope (Hitachi SU8010, Japan).…”

Molecularly Stimuli-Responsive Self-Assembled Peptide Nanoparticles for Targeted Imaging and Therapy

“…This conjugate was composed of kanamycin and a nonmembrane lytic antimicrobial peptide (P14LRR), which could form a cationic amphiphilic polyproline helix. Moreover, peptides, such as cationic host defense peptides (CHDP), also known as antimicrobial peptides (AMPs), have bactericidal effects by directly killing bacteria or affecting the dormitory against infection. , SAPs have great potential for combating drug-resistant bacterial infections . Cationic AMPs interact with negatively charged bacterial membranes, increasing membrane permeability, disrupting cell membranes, and releasing cell contents.…”

Antibacterial Chemodynamic Therapy: Materials and Strategies

“…Other therapeutic types have also been combined with Fe-based CDT for bacterial treatment [ 68 – 74 ].…”

“…Therefore, the synergy of peptide–drug therapy and CDT can be a viable antimicrobial strategy. For example, considering the fact that linoleic acid hydroperoxide (LAHP) has been reported to react with Fe(II) for 1 O 2 generation via the Fenton-like reaction to achieve CDT [ 76 ], Huang and coworkers [ 68 ] developed a multifunctional nanoplatform for bacterial suppression. They designed a D (KLAK) 2 peptide and conjugated linolic acid (which served as a hydrophobic moiety) to the N-terminus of the D (KLAK) 2 peptide to initiate the molecular self-assembly.…”