Muraymycin Nucleoside Antibiotics: Structure-Activity Relationship for Variations in the Nucleoside Unit

Abstract

Muraymycins are a subclass of naturally occurring nucleoside antibiotics with promising antibacterial activity. They inhibit the bacterial enzyme translocase I (MraY), a clinically yet unexploited target mediating an essential intracellular step of bacterial peptidoglycan biosynthesis. Several structurally simplified muraymycin analogues have already been synthesized for structure–activity relationship (SAR) studies. We now report on novel derivatives with unprecedented variations in the nucleoside unit. For the synthesis of these new muraymycin analogues, we employed a bipartite approach facilitating the introduction of different nucleosyl amino acid motifs. This also included thymidine- and 5-fluorouridine-derived nucleoside core structures. Using an in vitro assay for MraY activity, it was found that the introduction of substituents in the 5-position of the pyrimidine nucleobase led to a significant loss of inhibitory activity towards MraY. The loss of nucleobase aromaticity (by reduction of the uracil C5-C6 double bond) resulted in a ca. tenfold decrease in inhibitory potency. In contrast, removal of the 2′-hydroxy group furnished retained activity, thus demonstrating that modifications of the ribose moiety might be well-tolerated. Overall, these new SAR insights will guide the future design of novel muraymycin analogues for their potential development towards antibacterial drug candidates.

Merging Natural Products: Muraymycin–Sansanmycin Hybrid Structures as Novel Scaffolds for Potential Antibacterial Agents

“…The desired product 31 was then obtained in 64 % yield after aqueous workup and chromatographic purification. Finally, the secondary amine was Cbz‐deprotected under transfer hydrogenation conditions (1,4‐cyclohexadiene and Pd black in iso ‐propanol) to avoid unwanted reduction of the uracil C5‐C6 double bond [12b, 13b] . The identity of the obtained product was confirmed by LC‐MS analysis only, and the secondary amine was directly submitted to a final amide coupling with the m‐ tyrosine building block 19 .…”

Unexpected Seven-Membered Ring Formation for Muraymycin-Type Nucleoside-Peptide Antibiotics

“…Hence, we had envisioned to prepare uridine-derived building block 5 (see Scheme 2) that could then be connected to the solid phase. The design of 5 was based on our previously reported strategy to simplify the muraymycin core structure by omission of the 5′-substituent ("5′-deoxy" analogues) [30,33,[35][36][37][38]. Carboxylic acid 5 was intended to be attached to a trityl resin by formation of a trityl ester.…”

“…For muraymycins, a co-crystal structure in complex with MraY has been reported, enabling deeper insights into the inhibitor-target interaction [23][24][25]. However, experimental structure-activity relationship (SAR) studies are still crucial due to the pronounced conformational plasticity of MraY, and have therefore been carried out extensively as exemplified by the according work on muraymycins [26][27][28][29][30][31][32][33][34][35].…”

“…For muraymycins, a co-crystal structure in complex with MraY has been reported, enabling deeper insights into the inhibitor-target interaction [23][24][25]. However, experimental structure-activity relationship (SAR) studies are still crucial due to the pronounced conformational plasticity of MraY, and have therefore been carried out extensively as exemplified by the according work on muraymycins [26][27][28][29][30][31][32][33][34][35]. In contrast to previously reported solution-phase syntheses of muraymycin derivatives [28,30,31], we have recently described a solid phase-supported approach for the preparation of In contrast to previously reported solution-phase syntheses of muraymycin derivatives [28,30,31], we have recently described a solid phase-supported approach for the preparation of structurally Molbank 2020, 2020, M1122; doi:10.3390/M1122…”

Molecules from Side Reactions

“…For muraymycins, a co-crystal structure in complex with MraY has been reported, enabling deeper insights into the inhibitor-target interaction [23][24][25]. However, experimental structure-activity relationship (SAR) studies are still crucial due to the pronounced conformational plasticity of MraY, and have therefore been carried out extensively as exemplified by the according work on muraymycins [26][27][28][29][30][31][32][33][34][35]. In contrast to previously reported solution-phase syntheses of muraymycin derivatives [28,30,31], we have recently described a solid phase-supported approach for the preparation of structurally simplified muraymycin analogues [36].…”