Caprazamycins: Promising lead structures acting on a novel antibacterial target MraY

Abstract

The present status of antibiotic resistant requires an urgent invention of novel agents that act on clinically unexplored antibacterial targets. The enzyme MraY (phospho-MurNAcpentapeptide translocase), essential for bacterial cell wall synthesis, fulfils this criterion as it has not been explored as a target in a clinical context. Specifically, the enzyme is involved in the lipidlinked cycle of peptidoglycan biosynthesis and is reportedly targeted by naturally-occurring nucleoside antibiotics. The antimicrobial 'caprazamycin' class of nucleoside antibiotics targets Mycobacterium tuberculosis and clinically relevant Gram-negative bacteria such as Pseudomonas aeruginosa besides various drug resistant strains and is therefore an eligible starting point for the development of novel agents. In this review, we aim to summarise the structure-activity relationships of the natural, semi-synthetic as well as synthetic analogues of nucleoside antibiotic caprazamycins. This review highlights caprazamycins as promising lead structures for development of potent and selective antimicrobial agents that target MraY, the bacterial enzyme involved in the first membrane-dependent step in bacterial peptidoglycan assembly.

Uridine natural products: Challenging targets and inspiration for novel small molecule inhibitors

“…Prior to the total chemical synthesis of caprazamycin A, a mixture of caprazamycins (Scheme 2, 20) from fermentation were exploited for inhibitor development. 29,35 In these efforts, the caprazamycins were treated with aqueous acetic acid, to afford caprazene (21), a core scaffold amenable to diversification by chemical synthetic methods (Scheme 2). 36 The free amine was Boc-protected (22) and the carboxylic acid was coupled with either an amine or alcohol to produce a series of amides (23) and esters (24), respectively.…”

“…40,41 Then transthioesterification occurs and Pac4 catalyzes the amide bond formation of 28 and 31 with 32 to produce the final peptide fragment 33. The uridine modifications are initiated by oxidation of uridine (34) with Pac11 to the aldehyde (35). There are two possible mechanistic pathways to the dehydrated enamine uridine derivative (37) from 35.…”

Liposidomycin, the first reported nucleoside antibiotic inhibitor of peptidoglycan biosynthesis translocase I: The discovery of liposidomycin and related compounds with a perspective on their application to new antibiotics

“…Igarashi, who won the Sumiki-Umezawa Memorial Award in 2018 from the Japan Antibiotics Research Association with me [67], has summarized the study of caprazamycin, and Takahashi has described the first structure-activity relationship (SAR) of CRZEN-45 in this issue [68,69]. In addition, two reviews involving caprazamycin and the SARs of the derivatives were published recently in quick succession [65,70]. They revealed the essential pharmacophores present in the natural caprazamycin scaffold.…”

A Sub-Micromolar MraYAA Inhibitor with an Aminoribosyl Uridine Structure and a (S,S)-Tartaric Diamide: Synthesis, Biological Evaluation and Molecular Modeling

“…Currently, there are no MraY-directed antibiotics in clinical use, which is a key advantage to delay the occurrence of resistance. The synthesis of analogs of these peptidonucleosidic compounds has been the matter of intensive synthetic work [ 19 , 20 , 21 , 22 ], especially regarding the goal of decreasing their complexity while maintaining potent inhibition of MraY enzymatic activity. This is particularly challenging, considering the hydrophilicity of these molecules, and interesting progress has been achieved towards this objective [ 23 , 24 , 25 , 26 , 27 ].…”