The introduction of fluorine atoms or trifluoromethyl groups in short cationic peptides enhances their antimicrobial activity

Giménez, Diana; Andreu, Cecilia; Olmo, Marcel·lí del; Varea, Teresa; Díaz, M. Dolores; Asensio, Gregorio

doi:10.1016/j.bmc.2006.06.027

Cited by 49 publications

(35 citation statements)

References 41 publications

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“…1) found that raising the hydrophobicity of phenylalanine residues by replacing hydrogen atoms with fluorine atoms increased activity to be roughly equivalent to that for peptide sequences with tryptophan instead of 4-FPA. The most active peptides in this series contained two residues of BTF, the most heavily fluorinated and hydrophobic residue (23). All of the synthesized chains were reported to be nonhemolytic at 250 g/ml, though no hemolysis data were provided.…”

Section: Increasing Activitymentioning

confidence: 99%

Cationic Amphiphiles, a New Generation of Antimicrobials Inspired by the Natural Antimicrobial Peptide Scaffold

Findlay

Zhanel

Schweizer

2010

Antimicrob Agents Chemother

261

208

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2Naturally occurring cationic antimicrobial peptides (AMPs) and their mimics form a diverse class of antibacterial agents currently validated in preclinical and clinical settings for the treatment of infections caused by antimicrobial-resistant bacteria. Numerous studies with linear, cyclic, and diastereomeric AMPs have strongly supported the hypothesis that their physicochemical properties, rather than any specific amino acid sequence, are responsible for their microbiological activities. It is generally believed that the amphiphilic topology is essential for insertion into and disruption of the cytoplasmic membrane. In particular, the ability to rapidly kill bacteria and the relative difficulty with which bacteria develop resistance make AMPs and their mimics attractive targets for drug development. However, the therapeutic use of naturally occurring AMPs is hampered by the high manufacturing costs, poor pharmacokinetic properties, and low bacteriological efficacy in animal models. In order to overcome these problems, a variety of novel and structurally diverse cationic amphiphiles that mimic the amphiphilic topology of AMPs have recently appeared. Many of these compounds exhibit superior pharmacokinetic properties and reduced in vitro toxicity while retaining potent antibacterial activity against resistant and nonresistant bacteria. In summary, cationic amphiphiles promise to provide a new and rich source of diverse antibacterial lead structures in the years to come.The rise in antibiotic resistance among pathogenic bacteria and the declining rate of novel drug discovery are common concerns in medicine (66), driving research into new antibacterial classes and novel drugs in order to maintain the existing ability to treat infectious diseases, especially those caused by multidrug-resistant (MDR) organisms (49, 51).While the enzymatic inhibitors from which many of our strongest antibiotics are derived are highly effective in the microbial world, higher-order organisms do not appear to rely entirely on such selective inhibitors (27). These organisms instead produce a number of broad-range antimicrobial peptides (AMPs), which do not target any single molecule or process but instead associate with cellular membranes, resulting in depolarization, lysis, and cell death through a disruption of the membrane topology. A subset of these peptides is able to translocate into the cell and disrupt cellular processes, such as protein and DNA synthesis (33). AMPs play a key role in the human immune system, and mutations affecting their production and expression have been linked to diseases such as morbus Kostmann and Crohn's disease (56, 75).Membrane targeting offers advantages over standard methods of drug design and antibiotic activity due to the wide variety of active structures and a reduced development of resistance mechanisms (78). Nevertheless, potential cytotoxicity to the host cells remains a major unsolved challenge (43). Mutants resistant to AMPs have been developed in the laboratory (54); however, such mutants may ...

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Section: Increasing Activitymentioning

confidence: 99%

Cationic Amphiphiles, a New Generation of Antimicrobials Inspired by the Natural Antimicrobial Peptide Scaffold

Findlay

Zhanel

Schweizer

2010

Antimicrob Agents Chemother

261

208

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“…The 19 F labeling of [Glu(OMe) 7,18,19 ] ALM F50/5 was achieved by synthesis of the analog ALM9, wherein the hydrophobic Val 9 , situated in the middle of the sequence, was replaced by the hydrophobic and lipophobic Dab(Tfa) 9 residue (26,(40)(41)(42)(43). Here, we conducted a 19 F MAS solid-state NMR investigation of ALM9 to study its aggregation in 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) phospholipid membranes using the CODEX approach (38).…”

Section: Introductionmentioning

confidence: 99%

Alamethicin Supramolecular Organization in Lipid Membranes from 19F Solid-State NMR

Salnikov

Raya

Zotti

et al. 2016

Biophysical Journal

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Alamethicins (ALMs) are antimicrobial peptides of fungal origin. Their sequences are rich in hydrophobic amino acids and strongly interact with lipid membranes, where they cause a well-defined increase in conductivity. Therefore, the peptides are thought to form transmembrane helical bundles in which the more hydrophilic residues line a water-filled pore. Whereas the peptide has been well characterized in terms of secondary structure, membrane topology, and interactions, much fewer data are available regarding the quaternary arrangement of the helices within lipid bilayers. A new, to our knowledge, fluorine-labeled ALM derivative was prepared and characterized when reconstituted into phospholipid bilayers. As a part of these studies, C 19 F 3 -labeled compounds were characterized and calibrated for the first time, to our knowledge, for 19 F solid-state NMR distance and oligomerization measurements by centerband-only detection of exchange (CODEX) experiments, which opens up a large range of potential labeling schemes. The 19 F-19 F CODEX solid-state NMR experiments performed with ALM in POPC lipid bilayers and at peptide/lipid ratios of 1:13 are in excellent agreement with molecular-dynamics calculations of dynamic pentameric assemblies. When the peptide/lipid ratio was lowered to 1:30, ALM was found in the dimeric form, indicating that the supramolecular organization is tuned by equilibria that can be shifted by changes in environmental conditions.

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“…In an attempt to improve microbicidal activity of a selected peptide, general optimization strategies may be followed including cyclization [116], introduction of fluorine atoms or trifluoromethyl groups [117], increase of positive charge or hydrophobicity [118] or improving segregation of polar and hydrophobic residue starting from an helical projection [119]. Recent studies have investigated the effect of different basic residues on peptide antibacterial activity and cell selectivity [120].…”

Section: Optimization Strategies and High Throughput Screening Of Ampsmentioning

confidence: 99%

Antimicrobial peptides: an overview of a promising class of therapeutics

Giuliani¹,

Pirri²,

Nicoletto³

2007

Open Life Sciences

441

459

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Antibiotic resistance is increasing at a rate that far exceeds the pace of new development of drugs. Antimicrobial peptides, both synthetic and from natural sources, have raised interest as pathogens become resistant against conventional antibiotics. Indeed, one of the major strengths of this class of molecules is their ability to kill multidrug-resistant bacteria. Antimicrobial peptides are relatively small (6 to 100 aminoacids), amphipathic molecules of variable length, sequence and structure with activity against a wide range of microorganisms including bacteria, protozoa, yeast, fungi, viruses and even tumor cells. They usually act through relatively non-specific mechanisms resulting in membranolytic activity but they can also stimulate the innate immune response. Several peptides have already entered pre-clinical and clinical trials for the treatment of catheter site infections, cystic fibrosis, acne, wound healing and patients undergoing stem cell transplantation. We review the advantages of these molecules in clinical applications, their disadvantages including their low in vivo stability, high costs of production and the strategies for their discovery and optimization.

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The introduction of fluorine atoms or trifluoromethyl groups in short cationic peptides enhances their antimicrobial activity

Cited by 49 publications

References 41 publications

Cationic Amphiphiles, a New Generation of Antimicrobials Inspired by the Natural Antimicrobial Peptide Scaffold

Cationic Amphiphiles, a New Generation of Antimicrobials Inspired by the Natural Antimicrobial Peptide Scaffold

Alamethicin Supramolecular Organization in Lipid Membranes from 19F Solid-State NMR

Antimicrobial peptides: an overview of a promising class of therapeutics

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