1. Total Synthesis and Structural Elucidation of Ogipeptins
Shingo Takiguchi, Yuki Hirota-Takahata, Takahide Nishi Org Lett. 2022 Jul 15;24(27):4935-4938. doi: 10.1021/acs.orglett.2c01863. Epub 2022 Jul 7.
The first total synthesis of ogipeptin A was achieved. Recently, using the advanced Marfey's method, we determined the absolute configuration patterns of three β-hydroxy-α,γ-diaminobutyric acids (β-OH Dabs) composing ogipeptins. On the basis of this result, we conducted solid-phase total synthesis of three diastereomers of ogipeptin A. The analytical data of one diastereomer exactly corresponded with those of natural ogipeptin A. Therefore, the absolute configurations of ogipeptins have been elucidated.
2. Inactivation of Polymyxin by Hydrolytic Mechanism
Jianhua Yin, Gang Wang, Dan Cheng, Jianv Fu, Juanping Qiu, Zhiliang Yu Antimicrob Agents Chemother. 2019 May 24;63(6):e02378-18. doi: 10.1128/AAC.02378-18. Print 2019 Jun.
Polymyxins are nonribosomal peptide antibiotics used as the last-resort drug for treatment of multidrug-resistant Gram-negative bacteria. However, strains that are resistant to polymyxins have emerged in many countries. Although several mechanisms for polymyxin resistance have been well described, there is little knowledge on the hydrolytic mechanism of polymyxin. Here, we identified a polymyxin-inactivating enzyme from Bacillus licheniformis strain DC-1 which was produced and secreted into the medium during entry into stationary phase. After purification, sequencing, and heterologous expression, we found that the alkaline protease Apr is responsible for inactivation of polymyxins. Analysis of inactivation products demonstrated that Apr cleaves polymyxin E at two peptide bonds: one is between the tripeptide side chain and the cyclic heptapeptide ring, the other between l-Thr and l-α-γ-diaminobutyric acid (l-Dab) within the cyclic heptapeptide ring. Apr is highly conserved among several genera of Gram-positive bacteria, including Bacillus and Paenibacillus It is noteworthy that two peptidases S8 from Gram-negative bacteria shared high levels of sequence identity with Apr. Our results indicate that polymyxin resistance may result from inactivation of antibiotics by hydrolysis.
3. N-acyl-(alpha, gamma diaminobutyric acid)n hydrazide as an efficient gene transfer vector in mammalian cells in culture
J Y Legendre, A Trzeciak, D Bur, U Deuschle, A Supersaxo Pharm Res. 1997 May;14(5):619-24. doi: 10.1023/a:1012105128722.
Purpose: This study investigates the structure/activity relationship of a series of N-acyl-peptides (lipopeptides) for the transfection of mammalian cells. Methods: Lipopeptides comprising 1 to 3 basic amino-acids and a single fatty acid chain were synthesized. Transfecting complexes between lipopeptide, plasmid DNA and dioleoyl phosphatidylethanolamine were prepared and applied on cells in culture. Transfection efficiency was evaluated by measuring beta-galactosidase activity 48 h post-transfection. Lipopeptide-DNA binding was also investigated by physical means and molecular modelling. Results: Besides the length of the fatty acid chain, the nature of the basic amino-acid and the C-terminal group were crucial parameters for high transfection efficiency. The N-acyl-(diaminobutyric acid)n derivatives were the most potent transfecting agents among those tested and induced a beta-galactosidase activity 2 to 20 times higher than the N-acyl-lysine, -ornithine or -diaminopropionic acid derivatives. Furthermore, a hydrazide C-terminal modification greatly enhanced transfection efficiency for all compounds tested. The reason why alpha, gamma-diaminobutyric acid hydrazide-based lipopeptides were the most potent in transfection is not fully understood but could be related to their high DNA binding. Conclusions: Poly- or oligo-diaminobutyric acid containing or not a hydrazide C-terminus could advantageously be used in peptide-based gene delivery systems.
