Since the discovery of magainins, cecropins and defensins 30 years ago, antimicrobial peptides (AMPs) have been hailed as a potential solution to the dearth of novel antibiotic development. AMPs have shown robust activity against a wide variety of pathogens, including drug-resistant bacteria. Unlike small-molecule antibiotics, however, AMPs have failed to translate this success to the clinic. Only the polymyxins, gramicidins, nisin and daptomycin are currently approved for medical use; the latter is the only example to have been developed in the last several decades. Nonetheless, researchers continue to isolate, modify and develop novel AMPs for therapeutic applications. Efforts have focused on increasing stability, reducing cytotoxicity, improving antimicrobial activity and incorporating AMPs in novel formulations, including nanoscale particles. As peptide synthesis and recombinant production methodologies improve, and more relevant bioassays become available, it becomes increasingly likely that AMPs will break the regulatory barrier and enter the marketplace as valuable antimicrobial weapons in the next 10 years.

Road to clinical efficacy: challenges and novel strategies for antimicrobial peptide development

The transition of antimicrobial peptides (AMPs) from the laboratory to market has been severely hindered by their instability toward proteases in biological systems. In the present study, we synthesized derivatives of the cationic AMP Pep05 (KRLFKKLLKYLRKF) by substituting L-amino acid residues with D- and unnatural amino acids, such as D-lysine, D-arginine, L-2,4-diaminobutanoic acid (Dab), L-2,3-diaminopropionic acid (Dap), L-homoarginine, 4-aminobutanoic acid (Aib), and L-thienylalanine, and evaluated their antimicrobial activities, toxicities, and stabilities toward trypsin, plasma proteases, and secreted bacterial proteases. In addition to measuring changes in the concentration of the intact peptides, LC-MS was used to identify the degradation products of the modified AMPs in the presence of trypsin and plasma proteases to determine degradation pathways and examine whether the amino acid substitutions afforded improved proteolytic resistance. The results revealed that both D- and unnatural amino acids enhanced the stabilities of the peptides toward proteases. The derivative DP06, in which all of the L-lysine and L-arginine residues were replaced by D-amino acids, displayed remarkable stability and mild toxicity in vitro but only slight activity and severe toxicity in vivo, indicating a significant difference between the in vivo and in vitro results. Unexpectedly, we found that the incorporation of a single Aib residue at the N-terminus of compound UP09 afforded remarkably enhanced plasma stability and improved activity in vivo. Hence, this derivative may represent a candidate AMP for further optimization, providing a new strategy for the design of novel AMPs with improved bioavailability.

/pdf/d-and-unnatural-amino-acid-substituted-antimicrobial-34bnythtoy.pdf

D- and Unnatural Amino Acid Substituted Antimicrobial Peptides With Improved Proteolytic Resistance and Their Proteolytic Degradation Characteristics.

Conventional small-molecule antibiotics are facing a significant challenge of the rapidly developed drug resistance of pathogens. In contrast, antimicrobial peptides (AMPs), an important component for innate host defenses, are now under intensive investigation as a promising antimicrobial agent for combating drug resistant pathogens. Most AMPs can effectively kill a broad spectrum of pathogens via physical disruption of microbial cellular membranes, which is identified to be difficult to develop resistance. However, the clinical applications of AMPs are still greatly limited by several inherent impediments, such as high cost of production, potential hemolysis or toxicity, and liability to proteinase degradation. Recently, cationic poly(α-amino acid)s with structures mimicking the AMPs are found to have excellent antimicrobial activity. These polymers, termed "antimicrobial poly(α-amino acid)s (APAAs)," have some advantages over AMPs, such as easy production and modification, prolonged antimicrobial activity, low cytotoxicity, and enhanced stability to protease degradation. Here, a brief introduction of mechanisms and affecting factors of microbial killing by AMPs is first presented, followed by a systematic illustration of recent advances in design and preparation of biomimetic APAAs and a perspective in this field.

From Antimicrobial Peptides to Antimicrobial Poly(α-amino acid)s.

Nowadays a growing demand for green chemicals and cleantech solutions is motivating the industry to strive for biobased building blocks. We have identified the tertiary carbon atom-containing 2-hydroxyisobutyric acid (2-HIBA) as an interesting building block for polymer synthesis. Starting from this carboxylic acid, practically all compounds possessing the isobutane structure are accessible by simple chemical conversions, e. g. the commodity methacrylic acid as well as isobutylene glycol and oxide. During recent years, biotechnological routes to 2-HIBA acid have been proposed and significant progress in elucidating the underlying biochemistry has been made. Besides biohydrolysis and biooxidation, now a bioisomerization reaction can be employed, converting the common metabolite 3-hydroxybutyric acid to 2-HIBA by a novel cobalamin-dependent CoA-carbonyl mutase. The latter reaction has recently been discovered in the course of elucidating the degradation pathway of the groundwater pollutant methyl tert-butyl ether (MTBE) in the new bacterial species Aquincola tertiaricarbonis. This discovery opens the ground for developing a completely biotechnological process for producing 2-HIBA. The mutase enzyme has to be active in a suitable biological system producing 3-hydroxybutyryl-CoA, which is the precursor of the well-known bacterial bioplastic polyhydroxybutyrate (PHB). This connection to the PHB metabolism is a great advantage as its underlying biochemistry and physiology is well understood and can easily be adopted towards producing 2-HIBA. This review highlights the potential of these discoveries for a large-scale 2-HIBA biosynthesis from renewable carbon, replacing conventional chemistry as synthesis route and petrochemicals as carbon source.

/pdf/biosynthesis-of-2-hydroxyisobutyric-acid-2-hiba-from-1i02plwjos.pdf

Biosynthesis of 2-hydroxyisobutyric acid (2-HIBA) from renewable carbon

New potent antimicrobial peptides from the venom of Polistinae wasps and their analogs

Development of antimicrobial peptides has attracted considerable attention in recent years due to the excessive use of antibiotics, which has led to multiresistant bacteria. Cationic amphiphilic Aib-containing peptide models Ac-(Aib-Arg-Aib-Leu)(n)-NH2, n = 1-4, and sequential cationic polypeptides (Arg-X-Gly)(n), X = Ala, Val, Leu, were prepared and studied for their antimicrobial and hemolytic activity, as well as for their proteolytic stability. Ac-(Aib-Arg-Aib-Leu)(n)-NH2, n = 2, 3 and the polypeptide (Arg-Leu-Gly)(n) exhibited significant antimicrobial activity, and they were nontoxic at their MIC values and resistant, in particular the Aib-peptide models, to enzymatic degradation. The conformational characteristics of the peptide models were studied by circular dichroism (CD). Structure-activity relationship studies revealed the importance of the amphipathic alpha-helical conformation of the reported peptides in inducing antimicrobial effects. It is concluded that peptide models comprising cationic amino acids (Arg), helicogenic and noncoding residues (Aib) and/or hydrophobic and helix-promoting components (Leu) may lead to the development of antimicrobial therapeutics.

Design and synthesis of cationic Aib-containing antimicrobial peptides: conformational and biological studies

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Design and synthesis of cationic Aib-containing antimicrobial peptides: conformational and biological studies