Rufomycins or Ilamycins: Naming Clarifications and Definitive Structural Assignments

Abstract

Rufomycin and ilamycin are synonymous for the same class of cyclopeptides, currently encompassing 33 structurally characterized isolates and 9 semisynthetic derivatives. Elucidation of new structures prioritized the consolidation of the names and established the structures of four diastereoisomeric rufomycins with a 2-piperidinone, named rufomycins 4–7, including full 1H/13C NMR assignments. The characteristic HSQC cross-peak for the CH-5, the hemiaminal carbon in amino acid #5, allows assignment of the stereocenters C-4 and C-5 within this ring. Semisynthetic derivatives (rufomycinSS 1, 2, and 3) were prepared from a rufomycins 4 and 6 mixture to validate the structural assignments. Based on the X-ray crystal structures of rufomycins 2 and 4, considering the NMR differences of rufomycins 7 vs 4–6 compared to rufomycinSS 1 vs 2 and 3, and taking into account that two major conformers, A and B, occur in both rufomycinSS 2 and 3, structural modeling was pursued. Collectively, this paper discusses the NMR spectroscopic differences of the stereoisomers and their possible 3D conformers and correlates these with the anti-Mycobacterium tuberculosis activity. In addition, a look at the history prioritizes names and numbering schemes for this group of antibiotics and leads to consolidated nomenclature for all currently known members, natural and semisynthetic derivatives, and serves to accommodate future discoveries.

New Rufomycins from Streptomyces atratus MJM3502 Expand Anti-Mycobacterium tuberculosis Structure–Activity Relationships

“…Previous investigations of the Streptomyces atratus strain MJM3502, which was selected from ca. 7000 actinomycete cultures via a high-throughput screening campaign, led to the re-identification of a series of rufomycins and expanded their potential as anti-tuberculosis (TB) leads. − In general, they possess a 21-membered heptapeptide ring, created via the non-ribosomal peptide synthetase (NRPS), , and rufomycins 4–7 contain an additional in-chain cyclized 2-piperidinone. , A previous study expanded a series of rufomycins and preliminary anti-Mycobacterium tuberculosis ( Mtb ) structure–activity relationships (SARs). , Continued efforts to explore structural variants with possible anti-TB potential from MJM3502 have now resulted in the isolation and characterization of four new albeit minor rufomycins, each possessing novel carbon skeletons in the rufomycin class [rufomycins 56, 57, 58, and 61 ( 1 – 4 ); Figure ].…”

“…This was further corroborated by the HMBCs from AA1-H-2 (δ H 5.71, t, J = 7.7 Hz) to AA7-C-1 and AA5-C-5 (δ C 71.5). Collectively, compound 1 was assigned as the first rufomycin with transannular cross-linkage, possessing a [5,17] bicyclic scaffold and named rufomycin 56 following the recently consolidated naming system …”

Bathiapeptides: Polythiazole-Containing Peptides from a Marine Biofilm-Derived Bacillus sp.

“…Despite the above indications of purity, the 1 H NMR spectra of compounds 1 – 5 showed two sets of signals. This phenomenon is prevalent in macrocycle molecules, such as rolloamides, cyclochlorotine, swinhopeptolides, and rufomycins due to their flexible ring system usually affording two distinctive types of conformer. We performed the 1 H NMR experiments on the major metabolite (compound 1 ) under different temperatures, but both sets of signals were still present with some changes in their ratio (Figure S3).…”

Marine Cyclic Peptides: Antimicrobial Activity and Synthetic Strategies

“…The results of SAR study revealed that a hydrophobic and bulky neutral amino acid (i.e., γ-methylleucine), and a basic amino acid moiety (lysine or ornithine) were indispensable structural motifs for antifungal activity. In addition, the structure of the lipophilic side chain did not have a crucial effect on the activity, as long as the total number of carbons ranged between 9 and 11 [191].…”

“…Rufomycins A (102) and B (103), also known as ilamycins [191], are highly interesting marine cyclopeptides [192], isolated from marine Streptomyces sp. [192][193][194][195][196][197][198].…”