Spatial structure of polypeptide antibiotic polymyxin M in water was studied by one-and two-dimensional (COSY, COSY-45, RELAY) H NMR spectroscopy. Analysis of the signal spectral parameters revealed two intramolecular hydrogen bonds in the cyclic part of the molecule which was analogous to the structure of polymyxin B. However, configuration of both the beta-turns in the polymyxin M structure differed from that of the detected earlier beta-turns in the structure of polymyxin B.
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ACS Chem Biol
January 2025
Department of Life Science and Applied Chemistry, Graduate School of Engineering, Nagoya Institute of Technology, Gokiso-cho, Showa-ku, Nagoya, Aichi 466-8555, Japan.
Developing novel nonribosomal peptides (NRPs) requires a comprehensive understanding of the enzymes involved in their biosynthesis, particularly the substrate amino acid recognition mechanisms in the adenylation (A) domain. This study focused on the A domain responsible for adenylating l-2,4-diaminobutyric acid (l-Dab) within the synthetase of polymyxin, an NRP produced by NBRC3020. To date, investigations into recombinant proteins that selectively adenylate l-Dab─exploring substrate specificity and enzymatic activity parameters─have been limited to reports on A domains found in enzymes synthesizing l-Dab homopolymers (pldA from USE31 and pddA from NBRC15115), which remain exceedingly rare.
View Article and Find Full Text PDFInt J Antimicrob Agents
January 2025
Department of Pharmacy, Uppsala University, SE-75123, Uppsala, Sweden. Electronic address:
Objectives: To expand a translational pharmacokinetic-pharmacodynamic (PKPD) modelling approach for assessing the combined effect of polymyxin B and minocycline against Klebsiella pneumoniae.
Methods: A PKPD model developed based on in vitro static time-kill experiments of one strain (ARU613) was first translated to characterize that of a more susceptible strain (ARU705), and thereafter to dynamic time-kill experiments (both strains) and to a murine thigh infection model (ARU705 only). The PKPD model was updated stepwise using accumulated data.
ACS Appl Bio Mater
January 2025
School of Chemistry, Pharmacy and Food Biosciences, University of Reading, Whiteknights, Reading RG6 6AD, U.K.
A series of tripodal (three-arm) lysine-based peptides were designed and synthesized and their self-assembly properties in aqueous solution and antimicrobial activity were investigated. We compare the behaviors of homochiral tripodal peptides (KKY)K and a homologue containing the bulky aromatic fluorenylmethoxycarbonyl (Fmoc) group Fmoc-(KKY)K, and heterochiral analogues containing k (d-Lys), (kkY)K and Fmoc-(kkY)K. The molecular conformation and self-assembly in aqueous solutions were probed using various spectroscopic techniques, along with small-angle X-ray scattering (SAXS) and cryogenic-transmission electron microscopy (cryo-TEM).
View Article and Find Full Text PDFPathogens
November 2024
Smart Animal Bio Institute, Dankook University, Cheonan 31116, Republic of Korea.
The emergence of antibiotic-resistant () is a pressing threat in clinical settings. Colistin is currently a widely used treatment for multidrug-resistant , serving as the last line of defense. However, reports of colistin-resistant strains of have emerged, underscoring the urgent need to develop alternative medications to combat these serious pathogens.
View Article and Find Full Text PDFFront Microbiol
December 2024
Umeå Centre for Microbial Research (UCMR), Umeå University, Umeå, Sweden.
Lipoproteins are crucial for maintaining the structural integrity of bacterial membranes. In Gram-negative bacteria, the localization of lipoprotein (Lol) system facilitates the transport of these proteins from the inner membrane to the outer membrane. In , an ε-proteobacterium, lipoprotein transport differs significantly from the canonical and well-studied system in , particularly due to the absence of LolB and the use of a LolF homodimer instead of the LolCE heterodimer.
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