Conformational Analysis of an Antibacterial Cyclodepsipeptide Active against Mycobacterium tuberculosis by a Combined ROE and RDC Analysis. Issue 24 (9th March 2017)

• Record Type: Journal Article
• Authors: Fredersdorf, Maic; Kurz, Michael; Bauer, Armin; Ebert, Marc‐Olivier; Rigling, Carla; Lannes, Laurie; Thiele, Christina Marie
• Is Part Of: Chemistry. Volume 23:Issue 24(2017)
• Page Start: 5729
• Page End: 5735
• Publication Date: 2017-03-09
• Subjects: antibacterials -- cyclic peptides -- griselimycin -- methylgriselimycin -- NMR spectroscopy -- structure determination; Chemistry -- Periodicals; 540
• DOI: 10.1002/chem.201605143
• Languages: English
• ISSNs: 0947-6539

Abstract

Abstract: Griselimycin (GM) and methylgriselimycin (MGM), naturally produced by microorganisms of the genus Streptomyces, are cyclic depsipeptides composed of ten amino acids. They exhibit antibacterial activity against Mycobacterium species by inhibiting the sliding clamp of prokaryotic DNA polymerase III and are therefore considered as potential anti‐tuberculosis drugs. The difference between the peptides is the presence ofl ‐( R )‐4‐methyl‐proline in MGM instead ofl ‐proline in GM at position 8 of the amino acid sequence. Methylation increases both metabolic stability and activity of MGM compared to GM. To get deeper insight into the structure–activity relationship, the solution structure of the cyclic part of MGM was determined using rotating‐frame nuclear Overhauser effect (ROE) distance restraints and residual dipolar couplings (RDC). The structure of MGM in solution is compared to the structure of GM in a co‐crystal with DNA polymerase III subunit beta. As a result, a highly defined structural model of MGM is obtained, which shows related characteristics to the bound GM. Abstract : The solution structure of methylgriselimycin (MGM), an antituberculotic depsipeptide, was determined by means of rotating‐frame nuclear Overhauser effect (ROE) distance restraints and residual dipolar couplings (RDC). The backbone of the solution structure of MGM is similar to the crystal structure of parent molecule griselimycin (GM) bound to DNA polymerase III subunit‐beta. Small local differences were efficiently picked up by RDCs.