Novel Des-Fatty Acyl-Polymyxin B Derivatives with Pseudomonas aeruginosa-Specific Antimicrobial Activity

Sato, Yuki; Shindo, Mitsuno; Sakura, Naoki; Uchida, Yoshiki; Kato, Ikuo

doi:10.1248/cpb.59.597

Cited by 14 publications

(13 citation statements)

References 26 publications

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“…TP2 was used as a model peptide in the examination of the ability of 4 to guanidinylate an N-terminal primary amino group, which during initial experiments, appeared more difficult to convert than side-chain amines. Previous reports on N-terminal guanidinylation of peptides often employ substituted thiourea reagents (e.g., N , N ′-bis( tert -butoxycarbonyl)- S -methylisothiourea or 1,3-bis(benzyloxycarbonyl)-2-methyl-2-thiopseudourea) along with mercuric chloride (HgCl 2 ) as the desulfurizing agent. − This strategy is considered unsuitable for SPS because of the formation of an insoluble mercuric sulfide precipitate . Furthermore, these transformations are reported to require long reaction times or repeated procedures to reach complete conversion.…”

Section: Resultsmentioning

confidence: 99%

“…Furthermore, the guanidino functionality of arginine residues is crucial for the biological activity of many classes of peptides, for example, cell-penetrating peptides (CPPs) − and antimicrobial peptides (AMPs), − the subclasses of which also possess immunomodulatory properties . CPPs facilitate efficient delivery of cargo molecules across cell membranes with potential use in the treatment of bacterial infections − and cancer. , Similarly, guanidinium-rich peptoids have been investigated as molecular transporters in cellular drug delivery. − Guanidinylation may also generate analogues with improved pharmacological properties, for example, guanidinylated aminoglycosides have been shown to exhibit improved RNA-binding affinity that confers increased antibacterial activity. , Additionally, N-terminal guanidinylation of biologically active peptides can lead to increased antimicrobial activity, higher receptor binding affinity, , or prolonged stability in serum and plasma. , …”

Section: Introductionmentioning

confidence: 99%

“…25−28 Guanidinylation may also generate analogues with improved pharmacological properties, for example, guanidinylated aminoglycosides have been shown to exhibit improved RNA-binding affinity that confers increased antibacterial activity. 29,30 Additionally, N-terminal guanidinylation of biologically active peptides can lead to increased antimicrobial activity, 31 higher receptor binding affinity, 32,33 or prolonged stability in serum and plasma. 34,35 Efficient guanidinylation protocols for both small molecules and peptides are crucial to facilitate more advanced structure− activity studies, for example, the introduction of guanidino functionalities in peptides or peptidomimetics beyond simple insertion of commercially available guanidine-containing residues during assembly on the solid phase.…”

Section: ■ Introductionmentioning

confidence: 99%

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Evaluation of 1H-Triazole-1-[N,N′-Bis(tert-butoxycarbonyl)]carboxamidine in Solution-Phase and On-Resin Guanidinylation

2021

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Several guanidines and guanidinylated peptides have substantial potential as therapeutics, but efficient guanidinylation reagents are vital for easy access to these compounds. Presently, pyrazole-1-carboxamidine type reagents are commonly used in the transformations of amines into corresponding guanidines. Here, we report a comparative study of the utility of 1H-triazole-1-[N,N′-bis(tert-butoxycarbonyl)]carboxamidine, which was synthesized in two steps and readily upscaled to gram amounts. It exhibited excellent performance in solution-phase reactions, rapidly converting a set of representative aliphatic primary and unhindered secondary amines as well as aniline into the corresponding bis(tert-butoxycarbonyl)-protected guanidines. To enable a direct assessment of the reactivity of guanidinylation reagents, conversions were performed in deuterated solvents (d 7-DMF or d 8-THF), allowing for continuous analysis of the reaction mixtures by 1H and 13C NMR. Likewise, 1H-triazole-1-[N,N′-bis(tert-butoxycarbonyl)]carboxamidine proved to be a versatile reagent in solid-phase conversions, for example, a resin-bound test peptide (KFFKFFK) was fully guanidinylated in only 2 h by using 2 equivalents of the reagent per free amino group. Also, 1H-triazole-1-[N,N′-bis(tert-butoxycarbonyl)]carboxamidine proved capable of completely guanidinylating more sterically hindered N-terminal residues (e.g., N-methyl amino acids or a peptoid) in resin-bound peptides. Its superior reactivity and stability demonstrated under heating conditions make 1H-triazole-1-[N,N′-bis(tert-butoxycarbonyl)]carboxamidine a valuable guanidinylation reagent both in solution- and solid-phase synthesis.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: ■ Introductionmentioning

confidence: 99%

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Evaluation of 1H-Triazole-1-[N,N′-Bis(tert-butoxycarbonyl)]carboxamidine in Solution-Phase and On-Resin Guanidinylation

2021

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“…The Dap analog had reduced acute toxicity in mouse with an LD 50 of 23.5 μmol kg − 1 compared with 4.8 μmol kg − 1 for PMB. In a subsequent study, Sato et al 66 described further des-fatty acyl nonapeptides and even octapeptides. [Ser 3 ]-PMB(3-10) (3 g) was highlighted with a minimum inhibitory concentration (MIC) against P. aeruginosa of 2 μg ml − 1 compared with 1 μg ml − 1 for PMB and an LD 50 of 450 μmol kg − 1 .…”

Section: Des-fatty Acyl Polymyxin B Analoguesmentioning

confidence: 99%

Development of new polymyxin derivatives for multi-drug resistant Gram-negative infections

Brown¹,

Dawson²

2017

J Antibiot

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Over the last decade, there has been a resurgence of interest in polymyxins owing to the rapid rise in multi-drug resistant Gram-negative bacteria against which polymyxins offer a last-resort treatment. Although having excellent antibacterial activity, the clinical utility of polymyxins is limited by toxicity, especially renal toxicity. There is much interest therefore in developing polymyxin analogues with an improved therapeutic index. This review describes recent work aimed at improving the activity and/or reducing the toxicity of polymyxins. Consideration to providing activity against emerging strains with reduced susceptibility to polymyxins is also made.

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“…In contrast, the team led by Vaara at Northern Antibiotics have demonstrated antimicrobial potency for nonapeptide variants of Pmx in which the exocyclic fatty acyl-diaminobutyryl-threonyl-diaminobutyryl (FA-Dab 1 -Thr 2 -Dab 3 ) linear tripeptide segment of Pmx was substituted with a truncated fatty acyl-dipeptide motif (FA-Thr 2 -XX 3 , where XX = d -Thr or d -Ser), exemplified by their compound NAB739 [31]. More drastic changes have been reported, including des-fatty acyl derivatives [32,33], but such compounds usually lack intrinsic antimicrobial activity, and instead act as membrane sensitizers that potentiate the activity of other antibiotics. PMBN is an archetypal example [25,34].…”

Section: Introductionmentioning

confidence: 99%

Structure-Function Studies of Polymyxin B Lipononapeptides

et al. 2019

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The emerging threat of infections caused by highly drug-resistant bacteria has prompted a resurgence in the use of the lipodecapeptide antibiotics polymyxin B and colistin as last resort therapies. Given the emergence of resistance to these drugs, there has also been a renewed interest in the development of next generation polymyxins with improved therapeutic indices and spectra of action. We report structure-activity studies of 36 polymyxin lipononapeptides structurally characterised by an exocyclic FA-Thr2-Dab3 lipodipeptide motif instead of the native FA-Dab1-Thr2-Dab3 tripeptide motif found in polymyxin B, removing one of the positively charged residues believed to contribute to nephrotoxicity. The compounds were prepared by solid phase synthesis using an on-resin cyclisation approach, varying the fatty acid and the residues at position 2 (P2), P3 and P4, then assessing antimicrobial potency against a panel of Gram-negative bacteria, including polymyxin-resistant strains. Pairwise comparison of N-acyl nonapeptide and decapeptide analogues possessing different fatty acids demonstrated that antimicrobial potency is strongly influenced by the N-terminal L-Dab-1 residue, contingent upon the fatty acid. This study highlights that antimicrobial potency may be retained upon truncation of the N-terminal L-Dab-1 residue of the native exocyclic lipotripeptide motif found in polymyxin B. The strategy may aid in the design of next generation polymyxins.

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Novel Des-Fatty Acyl-Polymyxin B Derivatives with Pseudomonas aeruginosa-Specific Antimicrobial Activity

Cited by 14 publications

References 26 publications

Evaluation of 1H-Triazole-1-[N,N′-Bis(tert-butoxycarbonyl)]carboxamidine in Solution-Phase and On-Resin Guanidinylation

Evaluation of 1H-Triazole-1-[N,N′-Bis(tert-butoxycarbonyl)]carboxamidine in Solution-Phase and On-Resin Guanidinylation

Development of new polymyxin derivatives for multi-drug resistant Gram-negative infections

Structure-Function Studies of Polymyxin B Lipononapeptides

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