Isolation and Structure Elucidation of Thiazomycin

Abstract

Thiazolyl peptides are a class of rigid macrocyclic compounds richly populated with thiazole rings. They are highly potent antibiotics but none have been advanced to clinic due to poor aqueous solubility. Recent progress in this field prompted a reinvestigation leading to the isolation of a new thiazolyl peptide, thiazomycin, a congener of nocathiacins. Thiazomycin possesses an oxazolidine ring as part of the amino-sugar moiety in contrast to the dimethyl amino group present in nocathiacin I. The presence of the oxazolidine ring provides additional opportunities for chemical modifications that are not possible with other nocathiacins. Thiazomycin is extremely potent against Gram-positive bacteria both in vitro and in vivo. The titer of thiazomycin in the fermentation broth was very low compared to the nocathiacins I and III. The lower titer together with its sandwiched order of elution presented significant challenges in large scale purification of thiazomycin. This problem was resolved by the development of an innovative preferential protonation based one-and/or two-step chromatographic method, which was used for pilot plant scale purifications of thiazomycin. The isolation and structure elucidation of thiazomycin is herein described.

A comprehensive review of glycosylated bacterial natural products

“…Currently 21 thiazole glycosides have been reported from different Actinomycetes including Micromonospora , Amycolatopsis , Nocardia, Actinoplanes , and Amycolata . Regiospecificity of glycosylation among the thiazomycin-type members (which includes thiazomycins, 1083,1084 nocathiacins, 1085–1087 glycothiohexides, 1088,1089 philipimycins 1090 and S-54832-A series 1091 ) is restricted to the hydroxyl group of a modified glutamate residue (Glu), the C-4 of a thiazole ring (Thz-3) or a C-3 phenolic substitution of the unique 2,5,6-trithiazolyl-3-hydroxypyridine (Pyr) (Fig. 48).…”

Thiopeptide Antibiotics: Retrospective and Recent Advances

“…Remarkably, the first thiopeptide antibiotics isolated from a marine source were YM-266183 and YM-266184, discovered as late as 2003, in Japan [12]. During the last few years some more thiopeptides have been isolated and characterized; these include the thiazomycins (2007) [13,14,15,16], philipimycin (2008) [17], thiomuracins (2009) [18], TP-1161 (2010) [19,20], baringolin (2012) [21], and kocurin (2013) [22] (Figure 3). …”

Bioactive heterocycles containing endocyclic N-hydroxy groups

“…Furthermore, nocathiacin and thiazomycin antibiotics exhibited antibacterial activity by selective inhibition of protein synthesis through a direct interaction with the L11 protein and 23S rRNA of the bacterial 50S ribosome. Moreover, they did not show any cross-resistance to clinically used antibiotic classes, such as vancomycin, oxazolidinones and quinolones [89-91]. Similarly, thiazomycin A 48f selectively inhibited protein synthesis with IC 50 value of 0.7 μg/ml and it did not inhibit any other macromolecules as RNA, DNA, peptidoglycan, and phospholipid of S. aureus [92].…”