The antibacterial activity of peptide dendrimers and polymyxin B increases sharply above pH 7.4.
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ABSTRACT:
SUBMITTER: Cai X
PROVIDER: S-EPMC8186529 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Polymyxin B, used to treat infections caused by antibiotic-resistant Gram-negative bacteria, produces nephrotoxicity at its current dosage. We show that a combination of nonbactericidal concentration of this drug and lysophosphatidylcholine (LPC) potently inhibits growth of Salmonella and at least two other Gram-negative bacteria in vitro This combination makes bacterial membrane porous and causes degradation of DnaK, the regulator of protein folding. Polymyxin B-LPC combination may be an effective and safer regimen against drug-resistant bacteria.
| S-EPMC7674032 | biostudies-literature
Project description:Synthetic modifications have been made directly to the cyclic peptide core of polymyxin B, enabling the further understanding of structure activity relationships of this antimicrobial peptide. Such modified polymyxins are also substrates for enzymic hydrolysis, enabling the synthesis of a variety of semi-synthetic analogues, resulting in compounds with increased in vitro antibacterial activity.
| S-EPMC7215238 | biostudies-literature
Project description:We have investigated the antibacterial activity and cytotoxicity of a series of amino-terminated poly(amidoamine) (PAMAM) dendrimers modified with poly(ethylene glycol) (PEG) groups. The antibacterial activity of the PAMAM dendrimers and their derivatives against the common ocular pathogens, Pseudomonas aeruginosa and Staphylococcus aureus, was evaluated by their minimum inhibitory concentrations (MICs). For the unmodified third and fifth generation (G3 and G5) amino-terminated dendrimers, the MICs against both P. aeruginosa and S. aureus were in the range of 6.3-12.5 microg mL(-1), comparable to that of the antimicrobial peptide LL-37 (1.3-12.5 microg mL(-1)) and within the wide range of 0.047-128 microg mL(-1) for the fluoroquinolone antibiotics. PEGylation of the dendrimers decreased their antibacterial activities, especially for the Gram-positive bacteria (S. aureus). The reduction in potency is likely due to the decrease in the number of protonated amino groups and shielding of the positive charges by the PEG chains, thus decreasing the electrostatic interactions of the dendrimers with the negatively-charged bacterial surface. Interestingly, localization of a greater number of amino groups on G5 vs. G3 dendrimers did not improve the potency. Significantly, even a low degree of PEGylation, e.g. 6% with EG(11) on G3 dendrimer, greatly reduced the cytotoxicity towards human corneal epithelial cells while maintaining a high potency against P. aeruginosa. The cytotoxicity of the PEGylated dendrimers to host cells is much lower than that reported for antimicrobial peptides. Furthermore, the MICs of these dendrimers against P. aeruginosa are more than two orders of magnitude lower than other antimicrobial polymers reported to date. These results motivate further exploration of the potential of cationic dendrimers as a new class of antimicrobial agents that may be less likely to induce bacterial resistance than standard antibiotics.
| S-EPMC2965593 | biostudies-literature
Project description:An anionic amphiphilic dendrimer is reported that possesses increased cytotoxicological potency against prokaryotic cells compared to eukaryotic cells. The half-maximal effective concentration (EC50) for the dendrimer against Bacillus subtilis, a Gram-positive bacterial strain, was measured to be 4.1 x 10(-5) M, while that against human umbilical vein endothelial cells (HUVEC) was more than 36x greater at a value of 1.5 x 10(-3) M. EC50 ratios for two commercial amphiphiles, sodium dodecyl sulfate (SDS) and Triton X-100, in addition to a similar synthesized dendritic structure were at most only 3.8x greater. Furthermore, the observed EC50 values appear to be correlated to the critical aggregation constant (CAC) in solution suggesting a mechanism of action for these anionic amphiphilic dendrimers related to their supramolecular structures.
| S-EPMC2673084 | biostudies-literature
Project description:The antibacterial activity of a series of nitric oxide (NO)-releasing poly(propylene imine) (PPI) dendrimers was evaluated against both Gram-positive and Gram-negative pathogenic bacteria, including methicillin-resistant Staphylococcus aureus . A direct comparison of the bactericidal efficacy between NO-releasing and control PPI dendrimers (i.e., non-NO-releasing) revealed both enhanced biocidal action of NO-releasing dendrimers and reduced toxicity against mammalian fibroblast cells. Antibacterial activity for the NO donor-functionalized PPI dendrimers was shown to be a function of both dendrimer size (molecular weight) and exterior functionality. In addition to minimal toxicity against fibroblasts, NO-releasing PPI dendrimers modified with styrene oxide exhibited the greatest biocidal activity (?99.999% killing) against all bacterial strains tested. The N-diazeniumdiolate NO donor-functionalized PPI dendrimers presented in this study hold promise as effective NO-based therapeutics for combating bacterial infections.
| S-EPMC3482834 | biostudies-other
Project description:We have demonstrated that ivacaftor displays synergistic antibacterial activity in combination with polymyxin B against polymyxin-resistant Pseudomonas aeruginosa that commonly colonizes the lungs of people with cystic fibrosis (CF). However, the underlying mechanism(s) remain unclear. In the present study, we employed untargeted metabolomics to investigate the synergistic killing mechanism of polymyxin B in combination with ivacaftor against a polymyxin-susceptible P. aeruginosa FADDI-PA111 (polymyxin B MIC = 2 mg/L) and a polymyxin-resistant CF P. aeruginosa FADDI-PA006 (polymyxin B MIC = 8 mg/L). Metabolites were extracted at 3 h after treatments with polymyxin B alone (2 μg/mL for FADDI-PA111 and 4 μg/mL FADDI-PA006 P. aeruginosa), ivacaftor alone (8 μg/mL), and in combination. Polymyxin B monotherapy induced significant perturbations in the glycerophospholipid and fatty acid metabolism pathways against FADDI-PA111 and to a lesser extent in FADDI-PA006. In both strains, treatment with ivacaftor alone induced more pronounced perturbations in glycerophospholipid and fatty acid metabolism pathways than that with polymyxin B alone. This highlights the unique antimicrobial mode of action of ivacaftor. Pathway analysis revealed that in combination treatment, polymyxin B mediated killing is elevated by ivacaftor, largely due to the inhibition of cell envelope biogenesis via suppression of key membrane lipid metabolites (e.g., sn-glycerol 3-phosphate and sn-glycero-3-phosphoethanolamine) as well as perturbations in peptidoglycan and lipopolysaccharide biosynthesis. Furthermore, significant perturbations in the levels of amino sugars and nucleotide sugars, glycolysis, the tricarboxylic acid cycle, and pyrimidine ribonucleotide biogenesis were observed with the combination treatment. These findings provide novel mechanistic information on the synergistic antibacterial activity of polymyxin-ivacaftor combination.
| S-EPMC7296539 | biostudies-literature
Project description:Here the hypothesis that linearized esculentin 2EM (E2EM-lin) from Glandirana emeljanovi possesses pH dependent activity is investigated. The peptide showed weak activity against Gram-negative bacteria (MLCs ≥ 75.0 μM) but potent efficacy towards Gram-positive bacteria (MLCs ≤ 6.25 μM). E2EM-lin adopted an α-helical structure in the presence of bacterial membranes that increased as pH was increased from 6 to 8 (↑ 15.5-26.9%), whilst similar increases in pH enhanced the ability of the peptide to penetrate (↑ 2.3-5.1 mN m-1) and lyse (↑ 15.1-32.5%) these membranes. Theoretical analysis predicted that this membranolytic mechanism involved a tilted segment, that increased along the α-helical long axis of E2EM-lin (1-23) in the N → C direction, with - < µH > increasing overall from circa - 0.8 to - 0.3. In combination, these data showed that E2EM-lin killed bacteria via novel mechanisms that were enhanced by alkaline conditions and involved the formation of tilted and membranolytic, α-helical structure. The preference of E2EM-lin for Gram-positive bacteria over Gram-negative organisms was primarily driven by the superior ability of phosphatidylglycerol to induce α-helical structure in the peptide as compared to phosphatidylethanolamine. These data were used to generate a novel pore-forming model for the membranolytic activity of E2EM-lin, which would appear to be the first, major reported instance of pH dependent AMPs with alkaline optima using tilted structure to drive a pore-forming process. It is proposed that E2EM-lin has the potential for development to serve purposes ranging from therapeutic usage, such as chronic wound disinfection, to food preservation by killing food spoilage organisms.
| S-EPMC8382640 | biostudies-literature
Project description:To counteract the growing bacterial resistance, we previously reported the remarkable antimicrobial activity of amino acid-conjugated cationic dendrimers (CDs) against several Gram-negative species, establishing that the cationic lysine was essential for their potency. In this paper, CDs conjugated with lysine and arginine and encapsulating ursolic and oleanolic acids (UOACDs) were assumed to be excellent candidates for developing new antibacterial agents, possibly active against Gram-positive species. Indeed, both the guanidine group of arginine and the two triterpenoid acids are items known for directing antibacterial effects, particularly against Gram-positive bacteria. The cationic dendrimers were obtained by peripheral conjugation with the selected amino acids and by entrapping a physical mixture of the commercial triterpenoid acids. The cationic compounds were characterized and successfully tested against 15 Gram-positive isolates. Interesting minimum inhibitory concentration (MIC) values were obtained for all the dendrimer-drug agents, establishing that the antibacterial activity observed for the UOACDs strongly depended on the density and on the type of the cationic groups of the cationic amino acid-conjugated dendrimers and not on the presence and the release of UOA. Particularly, lysine was critical for potency, while arginine was critical for redirecting activity against Gram-positive species. Especially, a high cationic character, associated with a balanced content of lysine/arginine, produced a remarkable antimicrobial effect (MIC = 0.5-8.7 µM).
| S-EPMC7916190 | biostudies-literature
Project description:Antimicrobial peptides (AMPs) have been an area of great interest, due to the high selectivity of these molecules toward bacterial targets over host cells and the limited development of bacterial resistance to these molecules throughout evolution. Previous work showed that when Histidine was incorporated into the peptide C18G it lost antimicrobial activity. The role of pH on activity and biophysical properties of the peptide was investigated to explain this phenomenon. Minimal inhibitory concentration (MIC) results demonstrated that decreased media pH increased antimicrobial activity. Trichloroethanol (TCE) quenching and red-edge excitation spectroscopy (REES) showed a clear pH dependence on peptide aggregation in solution. Trp fluorescence was used to monitor binding to lipid vesicles and demonstrated the peptide binds to anionic bilayers at all pH values tested, however, binding to zwitterionic bilayers was enhanced at pH 7 and 8 (above the His pKa). Dual Quencher Analysis (DQA) confirmed the peptide inserted more deeply in PC:PG and PE:PG membranes, but could insert into PC bilayers at pH conditions above the His pKa. Bacterial membrane permeabilization assays which showed enhanced membrane permeabilization at pH 5 and 6 but vesicle leakage assays indicate enhanced permeabilization of PC and PC:PG bilayers at neutral pH. The results indicate the ionization of the His side chain affects the aggregation state of the peptide in solution and the conformation the peptide adopts when bound to bilayers, but there are likely more subtle influences of lipid composition and properties that impact the ability of the peptide to form pores in membranes.
| S-EPMC6721999 | biostudies-literature
Project description:A series of amphiphilic nitric oxide (NO)-releasing poly(amidoamine) (PAMAM) dendrimers with different exterior functionalities were synthesized by a ring-opening reaction between primary amines on the dendrimer and propylene oxide (PO), 1,2-epoxy-9-decene (ED), or a ratio of the two, followed by reaction with NO at 10 atm to produce N-diazeniumdiolate-modified scaffolds with a total storage of ~1 ?mol/mg. The hydrophobicity of the exterior functionality was tuned by varying the ratio of PO and ED grafted onto the dendrimers. The bactericidal efficacy of these NO-releasing vehicles against established Gram-negative Pseudomonas aeruginosa biofilms was then evaluated as a function of dendrimer exterior hydrophobicity (i.e., ratio of PO/ED), size (i.e., generation), and NO release. Both the size and exterior functionalization of dendrimer proved important to a number of parameters including dendrimer-bacteria association, NO delivery efficiency, bacteria membrane disruption, migration within the biofilm, and toxicity to mammalian cells. Although enhanced bactericidal efficacy was observed for the hydrophobic chains (e.g., ED), toxicity to L929 mouse fibroblast cells was also noted at concentrations necessary to reduce bacterial viability by 5-logs (99.999% killing). The optimal PO to ED ratios for biofilm eradication with minimal toxicity against L929 mouse fibroblast cells were 7:3 and 5:5. The study presented herein demonstrated the importance of both dendrimer size and exterior properties in determining efficacy against established biofilms without compromising biocompatibility to mammalian cells.
| S-EPMC3815563 | biostudies-literature