1. Fate of two 14C labelled muramyl peptides: Ac-Mur-L-Ala-gamma-D-Glu-meso-A2pm and Ac-Mur-L-Ala-gamma-D-Glu-meso-A2pm-D-Ala-D-Ala in mice. Evaluation of their ability to increase non specific resistance to Klebsiella infection
A Yapo, J F Petit, E Lederer, M Parant, F Parant, L Chedid Int J Immunopharmacol. 1982;4(3):143-9. doi: 10.1016/0192-0561(82)90042-x.
The metabolic fate in mice of two 14C labelled meso-A2pm containing muramyl-peptides, the muramyl-tripeptide (Ac-Mur-L-Ala-gamma-D-Glu-14C-meso-A2pm) (MTP) and the muramyl-pentapeptide (Ac-Mur-L-Ala-gamma-D-Glu-meso-A2pm-14C-D-Ala-14C-D-Ala) (MPP) has been studied. As with 14C-MDP, the radioactive muramyl-tripeptide and muramyl-pentapeptide disappear rapidly from the organs and the radioactivity is found mainly in the urine. In contrast to MDP, the two meso-A2pm containing muramyl-peptides are not excreted intact in the urine. In both cases labelled fragments have been identifed: meso-A2pm from MTP and the tetrapeptide gamma-D-Glu-meso-A2pm-D-Ala-D-Ala from MPP. The ability of the two muramyl-peptides to increase nonspecific resistance of mice to Klebsiella infection was also investigated. The muramyl-pentapeptide injected i.v. one day before a lethal dose of K. pneumoniae protects both adult and neonate mice, as does MDP itself; the muramyl-tripeptide is inactive.
2. Insights into Key Interactions between Vancomycin and Bacterial Cell Wall Structures
Feng Wang, Hongyu Zhou, Olatunde P Olademehin, Sung Joon Kim, Peng Tao ACS Omega. 2018 Jan 31;3(1):37-45. doi: 10.1021/acsomega.7b01483. Epub 2018 Jan 4.
Vancomycin is a glycopeptide antibiotic used for the treatment of serious infections by Gram-positive pathogens. Vancomycin inhibits cell wall biosynthesis by targeting the d-Ala-d-Ala terminus of peptidoglycan (PG). The highly cross-linked heptapeptide aglycon structure of vancomycin is the d-Ala-d-Ala binding site. The first residue of vancomycin is N-methyl-leucine, which is crucial for the dipeptide binding. The removal of N-methyl-leucine by Edman degradation results in desleucyl-vancomycin devoid of antimicrobial activities. To investigate the function of N-methyl-leucine for the dipeptide binding in vancomycin, molecular dynamics simulations of vancomycin and three N-terminus-modified vancomycin derivatives: desleucyl-vancomycin, vancomycinNtoC, and vancomycinSar, binding to a PG unit of the sequence l-Ala-d-iso-Gln-l-Lys-d-Ala-d-Ala with an intact pentaglycine bridge structure attached to the bridge link of l-Lys were carried out. Glycopeptide-PG binding interactions were characterized by root-mean-square-deviation contour analysis of atomic positions in vancomycin and its three analogues bound to a PG unit. The overall sampling space for four glycopeptide-PG complexes shows four distinct distributions with a continuous change between the conformational spaces. The hydrogen bond analyses show that multiple hydrogen bonds between the d-Ala-d-Ala and the vancomycin aglycon structure strengthened the dipeptide binding. The simulations revealed that the removal or chemical modification of N-methyl-leucine significantly weakens the dipeptide binding to the aglycon structure and provides interesting structural insights into glycopeptide-PG binding interactions.
3. The Carboxyl Terminus of Eremomycin Facilitates Binding to the Non-d-Ala-d-Ala Segment of the Peptidoglycan Pentapeptide Stem
James Chang, Hongyu Zhou, Maria Preobrazhenskaya, Peng Tao, Sung Joon Kim Biochemistry. 2016 Jun 21;55(24):3383-91. doi: 10.1021/acs.biochem.6b00188. Epub 2016 Jun 7.
Glycopeptide antibiotics inhibit cell wall biosynthesis in Gram-positive bacteria by targeting the peptidoglycan (PG) pentapeptide stem structure (l-Ala-d-iso-Gln-l-Lys-d-Ala-d-Ala). Structures of the glycopeptide complexed with a PG stem mimic have shown that the d-Ala-d-Ala segment is the primary drug binding site; however, biochemical evidence suggests that the glycopeptide-PG interaction involves more than d-Ala-d-Ala binding. Interactions of the glycopeptide with the non-d-Ala-d-Ala segment of the PG stem were investigated using solid-state nuclear magnetic resonance (NMR). LCTA-1421, a double (15)N-enriched eremomycin derivative with a C-terminal [(15)N]amide and [(15)N]Asn amide, was complexed with whole cells of Staphylococcus aureus grown in a defined medium containing l-[3-(13)C]Ala and d-[1-(13)C]Ala in the presence of alanine racemase inhibitor alaphosphin. (13)C{(15)N} and (15)N{(13)C} rotational-echo double-resonance (REDOR) NMR measurements determined the (13)C-(15)N internuclear distances between the [(15)N]Asn amide of LCTA-1421 and the (13)C atoms of the bound d-[1-(13)C]Ala-d-[1-(13)C]Ala to be 5.1 and 4.8 Å, respectively. These measurements also determined the distance from the C-terminal [(15)N]amide of LCTA-1421 to the l-[3-(13)C]Ala of PG to be 3.5 Å. The measured REDOR distance constraints position the C-terminus of the glycopeptide in the proximity of the l-Ala of the PG, suggesting that the C-terminus of the glycopeptide interacts near the l-Ala segment of the PG stem. In vivo REDOR measurements provided structural insight into how C-terminally modified glycopeptide antibiotics operate.
