Solubilized Gramicidin A as Potential Systemic Antibiotics

Wang, Fang; Qin, Luoheng; Pace, Christopher J.; Wong, P. T. T.; Malonis, Ryan J.; Gao, Jianmin

doi:10.1002/cbic.201100671

Cited by 57 publications

(71 citation statements)

References 40 publications

(14 reference statements)

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“…Nevertheless, systemic administration of gramicidin A may be possible in the near future. Chemical modification of gramicidin A has been shown to change the characteristics of the peptide enough to increase microbial targeting and/or decrease nonspecific toxicity (18,19,52,53), and encapsulation of gramicidin A within a targeted drug carriers such as nanoparticles may be a plausible method to safely deliver gramicidin A to only the tumor (54). Whether these approaches can be effectively applied to the use of gramicidin A as a novel cancer therapy is an essential area of future investigation.…”

Section: Discussionmentioning

confidence: 99%

“…Gramicidin A is a prototypical channel-forming ionophore that forms a 4-Å pore that can accommodate water, protons, and monovalent cations. Channel formation results in Na þ influx, K þ efflux, osmotic swelling, and cell lysis in biologic systems (18,19) and confers gramicidin A with potent antibiotic activity against gram-positive bacteria, fungi, and protozoa (20,21). We have previously demonstrated that gramicidin A is toxic to RCC cells and induces metabolic dysfunction and cellular energy depletion (22).…”

Section: Introductionmentioning

confidence: 99%

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Gramicidin A Blocks Tumor Growth and Angiogenesis through Inhibition of Hypoxia-Inducible Factor in Renal Cell Carcinoma

David

Owens

Inge

et al. 2014

Molecular Cancer Therapeutics

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Ionophores are hydrophobic organic molecules that disrupt cellular transmembrane potential by permeabilizing membranes to specific ions. Gramicidin A is a channel-forming ionophore that forms a hydrophilic membrane pore that permits the rapid passage of monovalent cations. Previously, we found that gramicidin A induces cellular energy stress and cell death in renal cell carcinoma (RCC) cell lines. RCC is a therapy-resistant cancer that is characterized by constitutive activation of the transcription factor hypoxia-inducible factor (HIF). Here, we demonstrate that gramicidin A inhibits HIF in RCC cells. We found that gramicidin A destabilized HIF-1a and HIF-2a proteins in both normoxic and hypoxic conditions, which in turn diminished HIF transcriptional activity and the expression of various hypoxia-response genes. Mechanistic examination revealed that gramicidin A accelerates O 2 -dependent downregulation of HIF by upregulating the expression of the von Hippel-Lindau (VHL) tumor suppressor protein, which targets hydroxylated HIF for proteasomal degradation. Furthermore, gramicidin A reduced the growth of human RCC xenograft tumors without causing significant toxicity in mice. Gramicidin A-treated tumors also displayed physiologic and molecular features consistent with the inhibition of HIF-dependent angiogenesis. Taken together, these results demonstrate a new role for gramicidin A as a potent inhibitor of HIF that reduces tumor growth and angiogenesis in VHLexpressing RCC. Mol Cancer Ther; 13(4); 788-99. Ó2014 AACR.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Gramicidin A Blocks Tumor Growth and Angiogenesis through Inhibition of Hypoxia-Inducible Factor in Renal Cell Carcinoma

David

Owens

Inge

et al. 2014

Molecular Cancer Therapeutics

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“…In contrast, GA-S1 and GA-L exhibited a combination of regular and distorted α-helical structures with a small fraction of disordered motives (< 5%). It is worth noting that the antibiotic activity of GA-S and GA-L is associated with β-sheet and α-helical conformation, respectively [24,38,39]. Therefore, the antimicrobial potency of GA-S2 and GA-L is expected to be preserved in ethanol, while that of GA-S1 could be affected by peptide-solvent interactions.…”

Section: Electrospinning Of Pe44 and Peptide Mixturesmentioning

confidence: 99%

“…From a functional point of view, GA is well known because of its activity as bactericide [22,23], antibiotic [24], and potential therapeutic agent for different carcinomas [25][26][27][28]. In spite of its potential biomedical applications, encapsulation of GA has been scarcely studied due to the insolubility of this peptide, which represents a major limitation [19,[29][30][31].…”

Section: Introductionmentioning

confidence: 99%

Antimicrobial Electrospun Fibers of Polyester Loaded with Engineered Cyclic Gramicidin Analogues

Maione

Valle

Pérez‐Madrigal

et al. 2017

Fibers

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Biodegradable polyester fibers have been loaded with two engineered analogues of gramicidin soviet. In these cyclic peptide derivatives, which were designed in a previous work to stabilize the bioactive conformation while enhancing the antimicrobial activity, the D-Phe was replaced by D-Pro, and the L-Pro was changed by 1-aminocyclopropanecarboxylic acid (Ac 3 c) or by an Ac 3 c derivative with two vicinal phenyl substituents in a trans relative disposition (S,S-c 3 diPhe). The diameter, topography, thermal stability and wettability of the polyester fibers, which have been obtained by electrospinning, strongly depend on the molecular constraints and stability of the loaded peptides. More specifically, unloaded and linear gramicidin-loaded fibers (used as control) are hydrophobic, rough and micrometric, while fibers loaded with the cyclic peptides are hydrophilic, ultra-smooth, nanometric and less thermally stable. The activity of the two cyclic peptides increases when loaded into polyester fibers, suggesting that the polymeric matrix stabilizes the bioactive β-sheet structure. The peptide with S,S-c 3 diPhe displays higher antibiotic potency and biocompatibility than that with Ac 3 c, which indicates not only that the bioactive conformation is better preserved by the former but also the significant role played by the phenyl rings in the recognition by living cells.

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“…Gramicidin A derivatives with the D-leucines at positions 10, 12 and 14 replaced by lysines have improved solubility in water and become cationic without altering the channel structure. These derivatives achieved bacterial specificity and low toxicity against mammalian cells [58].…”

Section: Bioactive Oligopeptidesmentioning

confidence: 99%

Development of biomaterial surfaces with and without microbial nanosegments

Alarfaj¹,

Lee²,

Munusamy

et al. 2015

Journal of Polymer Engineering

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Abstract Infections by microorganisms are a major problem in public health throughout the world. Artificial materials, including biomedical goods, inherently lack defense against microbial development. Therefore, microbial cells can adhere on any type of artificial surface, particularly in a moist environment, and start to multiply to form a huge population. In this review, we will discuss a strategy for designing antimicrobial polymers and antimicrobial surfaces. Generally, there are five types of antimicrobial polymers: (a) polymeric biocides, (b) biocidal polymers, (c) biocide-releasing polymers, (d) bioactive oligopeptides, and (e) antimicrobial surfaces. Antimicrobial surfaces preventing the growth of microorganisms are a promising method to inhibit the spread of microbial infections. The antimicrobial surfaces can reject the attachment of microbes and/or kill microbes in the vicinity and can be designed to kill microbes on contact. It is recommended that the material surface not release biocidal substances, therefore preventing exhaustion of biocide release to kill microbes. Furthermore, the antimicrobial surfaces are desired to be nontoxic to human cells. The development of contact-active antimicrobial surfaces by grafting antimicrobial nanosegments onto the material surface will be an important topic in the future.

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Solubilized Gramicidin A as Potential Systemic Antibiotics

Cited by 57 publications

References 40 publications

Gramicidin A Blocks Tumor Growth and Angiogenesis through Inhibition of Hypoxia-Inducible Factor in Renal Cell Carcinoma

Gramicidin A Blocks Tumor Growth and Angiogenesis through Inhibition of Hypoxia-Inducible Factor in Renal Cell Carcinoma

Antimicrobial Electrospun Fibers of Polyester Loaded with Engineered Cyclic Gramicidin Analogues

Development of biomaterial surfaces with and without microbial nanosegments

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