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1.
Heliyon ; 10(4): e26095, 2024 Feb 29.
Article in English | MEDLINE | ID: mdl-38420433

ABSTRACT

Here we present the development of nanoparticles (NPs) formulations specifically designed for targeting the antiapoptotic Bcl-2 proteins on the outer membrane of mitochondria with the drug agent ABT-737. The NPs which are self-assembled by the natural polypeptide poly gamma glutamic acid (ϒPGA) and a designed cationic and amphiphilic peptide (PFK) have been shown to target drugs toward mitochondria. In this study we systematically developed the formulation of such NPs loaded with the ABT-737 and demonstrated the cytotoxic effect of the best identified formulation on MDA-MB-231 cells. Our findings emphasize the critical role of solutions pH and the charged state of the components throughout the formulation process as well as the concentrations of the co-components and their mixing sequence, in achieving the most stable and effective cytotoxic formulation. Our study highlights the potential versatility of designed peptides in combination with biopolymers for improving drug delivery formulations and enhance their targeting abilities.

2.
Nat Commun ; 14(1): 8198, 2023 Dec 11.
Article in English | MEDLINE | ID: mdl-38081813

ABSTRACT

Antibiotic resistance of bacteria is considered one of the most alarming developments in modern medicine. While varied pathways for bacteria acquiring antibiotic resistance have been identified, there still are open questions concerning the mechanisms underlying resistance. Here, we show that alpha phenol-soluble modulins (PSMαs), functional bacterial amyloids secreted by Staphylococcus aureus, catalyze hydrolysis of ß-lactams, a prominent class of antibiotic compounds. Specifically, we show that PSMα2 and, particularly, PSMα3 catalyze hydrolysis of the amide-like bond of the four membered ß-lactam ring of nitrocefin, an antibiotic ß-lactam surrogate. Examination of the catalytic activities of several PSMα3 variants allowed mapping of the active sites on the amyloid fibrils' surface, specifically underscoring the key roles of the cross-α fibril organization, and the combined electrostatic and nucleophilic functions of the lysine arrays. Molecular dynamics simulations further illuminate the structural features of ß-lactam association upon the fibril surface. Complementary experimental data underscore the generality of the functional amyloid-mediated catalytic phenomenon, demonstrating hydrolysis of clinically employed ß-lactams by PSMα3 fibrils, and illustrating antibiotic degradation in actual S. aureus biofilms and live bacteria environments. Overall, this study unveils functional amyloids as catalytic agents inducing degradation of ß-lactam antibiotics, underlying possible antibiotic resistance mechanisms associated with bacterial biofilms.


Subject(s)
Staphylococcal Infections , Staphylococcus aureus , Humans , beta Lactam Antibiotics , Anti-Bacterial Agents/pharmacology , Anti-Bacterial Agents/metabolism , Monobactams/metabolism , beta-Lactams/pharmacology , beta-Lactams/metabolism , Staphylococcal Infections/microbiology , Bacteria
3.
ACS Biomater Sci Eng ; 9(1): 352-362, 2023 01 09.
Article in English | MEDLINE | ID: mdl-36521024

ABSTRACT

The growing resistance of pathogenic bacteria to conventional antibiotics promotes the development of new antimicrobial agents, including peptides. Hydrogels composed of antimicrobial peptides (AMPs) may be applied as topical treatments for skin infection and wound regeneration. The unique antimicrobial and ultrashort-peptide FKF (Phe-Lys-Phe) was recently demonstrated to form bactericidal hydrogels. Here, we sought to improve the cyto-biocompatibility of FKF by combining FKF hydrogels with gelatin. Homogeneous hybrid hydrogels of FKF:gelatin were developed based on a series of self-assembly steps that involved mixing solutions of the two components with no covalent cross-linkers. The hydrogels were characterized for their structural features, dissolution, cyto-biocompatibility, and antibacterial properties. These hybrid hydrogels first release the antibacterial FKF assemblies, leaving the gelatinous fraction of the hydrogel to serve as a scaffold for tissue regeneration. Sponges of these hybrid hydrogels, obtained by lyophilization and rehydrated prior to application, exhibited enhanced antimicrobial activity compared to the hydrogels' formulations.


Subject(s)
Anti-Infective Agents , Hydrogels , Hydrogels/pharmacology , Hydrogels/chemistry , Gelatin/pharmacology , Gelatin/chemistry , Peptides/pharmacology , Peptides/chemistry , Anti-Infective Agents/pharmacology , Anti-Bacterial Agents/pharmacology
4.
Acta Biomater ; 125: 231-241, 2021 04 15.
Article in English | MEDLINE | ID: mdl-33607306

ABSTRACT

The race drawn against bacteria facing the evolution of antimicrobial resistance fuels research for new drugs and therapeutic strategies. FKF, a tripeptide that is cationic and amphiphilic was examined in light of its potential antimicrobial activity. Acid titration of purified peptide solution, 6% w/v (136 mM), yielded a hydrogel at pH~ 4. Cryo-TEM images of FKF revealed distinct phases formed upon increase in pH, ranging from elongated needles, uniform width fibers, sheets and tubular structures. 1H NMR attested FKF charged states as function of pH, and CD and FTIR measurements indicated that FKF ß-sheet assemblies are held by both π-π stacking and H-bonds. FKF hydrogel displayed bactericidal activity against E. coli and P. aeruginosa with a 3-log reduction in bacterial counts. The hydrogel was also found effective in reducing P. aeruginosa contamination in a skin lesion model in rats. FKF forms a unique antimicrobial peptide-hydrogel, showing neglectable effect in dissolved state, yet only when fibrillary assembled it gains functionality. STATEMENT OF SIGNIFICANCE: Ultra-short peptides are at the frontier of peptide self-assembly research. The tripeptide FKF assumes distinct assembly forms that are a function of pH, for which we have pinpointed the accompanying changes in charge. Made of natural amino acids, FKF forms a pure peptide hydrogel phase, which is intrinsically antimicrobial. We demonstrate that antimicrobial effect is only assumed by the peptide assemblies, posing self-assembly as a pre-requisite for FKF's bactericidal effect. This system provides evidence for the link between specific microscopic peptide assembled structures, macroscopic gel formation and antimicrobial effect, utilized to alleviate bacterial contamination in vivo.


Subject(s)
Anti-Infective Agents , Escherichia coli , Animals , Anti-Bacterial Agents/pharmacology , Peptides , Protein Conformation, beta-Strand , Rats
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