Chemical logic of MraY inhibition by antibacterial nucleoside natural products

Abstract

Novel antibacterial agents are needed to address the emergence of global antibiotic resistance. MraY is a promising candidate for antibiotic development because it is the target of five classes of naturally occurring nucleoside inhibitors with potent antibacterial activity. Although these natural products share a common uridine moiety, their core structures vary substantially and they exhibit different activity profiles. An incomplete understanding of the structural and mechanistic basis of MraY inhibition has hindered the translation of these compounds to the clinic. Here we present crystal structures of MraY in complex with representative members of the liposidomycin/caprazamycin, capuramycin, and mureidomycin classes of nucleoside inhibitors. Our structures reveal cryptic druggable hot spots in the shallow inhibitor binding site of MraY that were not previously appreciated. Structural analyses of nucleoside inhibitor binding provide insights into the chemical logic of MraY inhibition, which can guide novel approaches to MraY-targeted antibiotic design.

Theoretical Study of Intermolecular Interactions between Critical Residues of Membrane Protein MraYAAand Promising Antibiotic Muraymycin D2

“…Thus, the face-to-face π-stacking interaction of the aromatic ring of Phe262 with the uracil base of MD2, tunicamycin, capuramycin, 3′-hydroxymureidomycin A, and carbacaprazamycin influences significantly their stacking inside this active site. 41 In addition to these three critical points, H37···Cε2 BCP exists between the ribose ring and the aromatic ring of Phe262. Consequently, they are involved in a weak unconventional C37–H37···Cε2 H-bond together ( Table 1 ).…”

“…As a consequence, Gly264 is not only another key residue in this active site but also a crucial amino acid in complex with capuramycin. 41 …”

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

“…This suggests that the primary amine in 15 might not be ideally spatially oriented yet to mediate a more pronounced interaction with the uridine‐adjacent pocket. In the case of 3′‐hydroxymureidomycin A (i.e., a 3′‐hydroxylated analog of 10 with a m‐ tyrosine unit at the same position as in 15 ), hydrogen bonds of the hydroxy group and the amine of the m‐ tyrosine moiety with T75 and D265 of MraY have been observed by X‐ray crystallography [11c] . On the other hand, the fact that 34 also was found to be a reasonably potent MraY inhibitor further supports our hypothesis that structural variations on the newly established scaffold of type 15 will be feasible.…”

“…Two defined binding pockets for the uracil and the 5′‐aminoribose moieties were identified, whereas the peptide unit is positioned on the surface of the protein. Recently, Lee and colleagues reported an even more detailed and comprehensive binding model for the inhibition of MraY by several nucleoside antibiotics, based on a range of X‐ray co‐crystal structures [11c] . Thereby, they identified common binding sites addressed by multiple sub‐classes of nucleoside antibiotics as well as unique sites for the binding of some sub‐classes, all on the cytosolic side of MraY.…”

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

“…The combination of organic synthesis and biosynthesis, aided by newly enabled structural studies of liposidomycin/ caprazamycin-MraY and/or CPZEN-45-WecA membrane proteins-drug complexes, can be expected to yield new types of antibiotics in the future (Fig. 6) [92,93].…”