Polycationic Gramicidin S Analogues with Both High Antibiotic Activity and Very Low Hemolytic Activity

Tamaki, Makoto; Harada, T.; Fujinuma, Kenta; Takanashi, Kazumasa; Shindo, Mitsuno; Kimura, Masahiro; Uchida, Yoshiki

doi:10.1248/cpb.c12-00290

Cited by 16 publications

(19 citation statements)

References 21 publications

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“…Previous studies have shown that self-assembling nanoantibiotics effectively localize antibiotics to the periplasmic space, thus allowing them to exert their bacterial activities against gram-negative bacteria. 9,10,29 In an attempt to augment and hone this strategy, biodegradable hydrophobic copolymers of PLGA have been attached to the N-termini of BA to design a novel class of selfassembling nano-BAs. Compared with other compounds, such as fatty acids, PLGA has attracted considerable attention for its attractive characteristics: 1) biodegradability and biocompatibility, 2) US Food and Drug Administration and European Medicine Agency approval in drug delivery systems for parenteral administration, 3) well-described formulations and methods of production adapted to various types of drugs (eg, hydrophilic or hydrophobic small molecules or macromolecules), 4) ability to modify surface properties to provide stealth and/or better interaction with biological materials, and 5) ability to target nanoparticles to specific organs or cells.…”

Section: Discussionmentioning

confidence: 99%

Synthesis, construction, and evaluation of self-assembled nano-bacitracin A as an efficient antibacterial agent in vitro and in vivo

Hong

Gao

Qiu

et al. 2017

IJN

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Bacitracin A (BA) is an excellent polypeptide antibiotic that is active against gram-positive bacteria without triggering multidrug resistance. However, BA is inactive against gram-negative bacteria because of its inability to cross the outer membrane of these cells, and it has strong nephrotoxicity, thus limiting its clinical applications. Nanoantibiotics can effectively localize antibiotics to the periplasmic space of bacteria while decreasing the adverse effects of antibiotics. In this study, biodegradable hydrophobic copolymers of poly ( d , l -lactide-co-glycolide) (PLGA) were attached to the N-termini of BA to design a novel class of self-assembled nano-bacitracin A (nano-BAs), and their potential as antibacterial agents was evaluated in vitro and in vivo. Nano-BAs had a core-shell structure with a mean diameter <150 nm. Impressively, nano-BAs had strong antibacterial properties against both gram-positive and gram-negative bacteria, and the distribution of antibacterial activity as a function of PLGA block length was skewed toward longer PLGA chains. No cytotoxicity against HK-2 cells or human red blood cells (hRBCs) was observed in vitro, suggesting good biocompatibility. A high local density of BA mass on the surface promoted endocytotic cellular uptake, and hydrophobic interactions between the PLGA block and lipopolysaccharide (LPS) facilitated the uptake of nano-BAs, thereby leading to greater antibacterial activities. In addition, Nano-BA 5K was found to be effective in vivo, and it served as an anti-infective agent for wound healing. Collectively, this study provides a cost-effective means of developing self-assembling nano-polypeptide antibiotic candidates with a broader antibacterial spectrum and a lower toxicity than commercially available peptide antibiotics, owing to their modification with biodegradable copolymers.

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Section: Discussionmentioning

confidence: 99%

Synthesis, construction, and evaluation of self-assembled nano-bacitracin A as an efficient antibacterial agent in vitro and in vivo

Hong

Gao

Qiu

et al. 2017

IJN

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“…The latter one (due to its positive charges) is potentially capable of cooperatively coupling in an aqueous solution with negatively charged membrane of a microbial cell. Such powerful multipoint electrostatic interaction is actively used in modern polycationic antiseptics [ 22 ].…”

Section: Discussionmentioning

confidence: 99%

NonToxic Silver/Poly-1-Vinyl-1,2,4-Triazole Nanocomposite Materials with Antibacterial Activity

et al. 2020

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Novel silver/poly-1-vinyl-1,2,4-triazole nanocomposite materials—possessing antimicrobial activity against Gram-positive and Gram-negative bacteria—have been synthesized and characterized in the solid state and aqueous solution by complex of modern physical-chemical and biologic methods. TEM-monitoring has revealed the main stages of microbial cell (E. coli) destruction by novel nanocomposite. The concept of direct polarized destruction of microbes by nanosilver proposed by the authors allows the relationship between physicochemical and antimicrobial properties of novel nanocomposites. At the same time, it was shown that the nanocomposite was nontoxic to the fibroblast cell culture. Thus, the synthesized nanocomposite combining antibacterial activity against Gram-positive and Gram-negative bacteria as well as the absence of toxic effects on mammalian cells is a promising material for the development of catheters, coatings for medical devices.

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“…Extensive studies have shown that seemingly subtle changes in the β-turn region could have a dramatic impact on the antimicrobial activity, suggesting that this region may be a hot spot for modulating GS structure and activity. Interestingly, the effect of these modifications on the antimicrobial activity is often not correlated with the cytotoxicity. ,− Two general methods have been adopted for β-turn region modifications: one involves the modification of D Phe and/or Pro residues, while the other involves replacement of the entire D Phe-Pro sequence with dipeptide surrogates.…”

Section: Structure–activity Relationship Of Gramicidin S and Its Anal...mentioning

confidence: 99%

“…Investigations of GS analogues with a modified β-turn region have indicated that the hydrophobic aromaticity is critical for maintaining the antimicrobial activity, , with only a few exceptions . Impressively, extra amino groups on Pro often resulted in decreased hemolytic activity while largely maintaining the antimicrobial activity, leading to a popular modification strategy .…”

Section: Structure–activity Relationship Of Gramicidin S and Its Anal...mentioning

confidence: 99%

Recent Advances in the Exploration of Therapeutic Analogues of Gramicidin S, an Old but Still Potent Antimicrobial Peptide

et al. 2019

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Gramicidin S (GS), one of the oldest commercially used peptide antibiotics, is known for its robust antibacterial activity against both Gram-positive and Gram-negative bacterial strains. Although it was discovered well over 70 years ago, its clinical potential was limited to topical applications because of its high hemolytic activity. To overcome this side effect, significant efforts have been invested in the chase for GS analogues with high therapeutic index (e.g., high antimicrobial activity and low hemolytic activity) in the past decades. In this Perspective, the structural properties and biological profiles (including the recently discovered activities) of representative GS analogues designed by different approaches are described and analyzed. We also present how the general structure–activity relationships were established and how they could help in the design of more efficient GS analogues.

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Polycationic Gramicidin S Analogues with Both High Antibiotic Activity and Very Low Hemolytic Activity

Abstract: and Pro 5,5′ residues whose modification will significantly increase the therapeutic index.

Cited by 16 publications

References 21 publications

Synthesis, construction, and evaluation of self-assembled nano-bacitracin A as an efficient antibacterial agent in vitro and in vivo

Synthesis, construction, and evaluation of self-assembled nano-bacitracin A as an efficient antibacterial agent in vitro and in vivo

NonToxic Silver/Poly-1-Vinyl-1,2,4-Triazole Nanocomposite Materials with Antibacterial Activity

Recent Advances in the Exploration of Therapeutic Analogues of Gramicidin S, an Old but Still Potent Antimicrobial Peptide

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