Acetylenic Replacement of Albicidin's Methacrylamide Residue Circumvents Detrimental E/Z Photoisomerization and Preserves Antibacterial Activity.

Iraj Behroz,Kay Hommernick,Roderich D Süssmuth,Leonardo Kleebauer,Andi Mainz,Maria Seidel,Stefan Grätz,John B Weston

doi:10.1002/chem.202100523

Abstract

The natural product albicidin is a highly potent inhibitor of bacterial DNA gyrase. Its outstanding activity, particularly against Gram‐negative pathogens, qualifies it as a promising lead structure in the search for new antibacterial drugs. However, as we show here, the N‐terminal cinnamoyl moiety of albicidin is susceptible to photochemical E/Z isomerization. Moreover, the newly formed Z isomer exhibits significantly reduced antibacterial activity, which hampers the development and biological evaluation of albicidin and potent derivatives thereof. Hence, we synthesized 13 different variants of albicidin in which the vulnerable para‐coumaric acid moiety was replaced; this yielded photostable analogues. Biological activity assays revealed that diaryl alkyne analogues exhibited virtually undiminished antibacterial efficacy. This promising scaffold will therefore serve as a blueprint for the design of a potent albicidin‐based drug.

Highlights

The global spread of antimicrobial resistance (AMR) increasingly renders medications used to treat life-threatening infections ineffective and poses an imminent danger to millions of people.[1,2] Even the strongest weapons in our therapeutic arsenal, such as polymyxins and carbapenems, are facing limitations due to the incessant emergence of pan-resistant pathogenic bacteria.[3,4] Due to their highly restrictive outermembrane permeability, Gram-negative microorganisms are of particular concern.[5]
To demonstrate the photochemical (E)-(Z)-isomerization for the cinnamoyl residue of albicidin, a solution of freshly prepared albicidin (1) in [D6]DMSO was exposed to UV light (λ = 366 nm) in a time-dependent manner and monitored by 1H NMR spectroscopy (Figure 2)
Depending on the bacterial strain, the Z isomer exhibited a five- to tenfold decline in antibacterial activity compared to the well-characterized E isomer of albicidin

Summary

Introduction

The global spread of antimicrobial resistance (AMR) increasingly renders medications used to treat life-threatening infections ineffective and poses an imminent danger to millions of people.[1,2] Even the strongest weapons in our therapeutic arsenal, such as polymyxins and carbapenems, are facing limitations due to the incessant emergence of pan-resistant pathogenic bacteria.[3,4] Due to their highly restrictive outermembrane permeability, Gram-negative microorganisms are of particular concern.[5]. Cinnamates and their hydroxy derivatives, including para-coumaric acid, caffeic acid, ferulic acid, and sinapic acid, have been shown to rapidly undergo light-induced E/Z isomerization and dimerization, for example, in plant cell walls The former two are known to isomerize from the E form to the Z form, and to a lesser degree in the opposite direction, to form an equilibrium mixture in which the E isomer is the main component.[27,28,29,30] The photoisomerization of cinnamides is highly dependent on both N-alkylation and aromatic substitution.[31,32] In 1985, Birch and Patil had observed that albicidin gradually converted into another compound when stored in methanol at room temperature. Because of the knowledge and application of alkynes in medicinal chemistry, we were interested in assessing their applicability for structural variations of the antibacterial albicidin

Results and Discussion

Conclusion

Conflict of Interest