During their lifetime almost half of women will experience a symptomatic urinary tract infection (UTI) with a further half experiencing a relapse within six months. Currently UTIs are treated with antibiotics, but increasing antibiotic resistance rates highlight the need for new treatments. Uropathogenic Escherichia coli (UPEC) is responsible for the majority of symptomatic UTI cases and thus has become a key pathological target. Adhesion of type one pilus subunit FimH at the surface of UPEC strains to mannose‐saturated oligosaccharides located on the urothelium is critical to pathogenesis. Since the identification of FimH as a therapeutic target in the late 1980s, a substantial body of research has been generated focusing on the development of FimH‐targeting mannose‐based anti‐adhesion therapies. In this review we will discuss the design of different classes of these mannose‐based compounds and their utility and potential as UPEC therapeutics.

Site-selective chemical methods for protein bioconjugation have revolutionized the fields of cell and chemical biology through the development of novel protein/enzyme probes bearing fluorescent, spectroscopic, or even toxic cargos. Herein, we report two new methods for the bioconjugation of α-oxo aldehyde handles within proteins using small molecule aniline and/or phenol probes. The “α-oxo-Mannich” and “catalyst-free aldol” ligations both compete for the electrophilic α-oxo aldehyde, which displays pH divergent reactivity proceeding through the “Mannich” pathway at acidic pH to afford bifunctionalized bioconjugates, and the “catalyst-free aldol” pathway at neutral pH to afford monofunctionalized bioconjugates. We explore the substrate scope and utility of both of these bioconjugations in the construction of neoglycoproteins, in the process formulating a mechanistic rationale for how both pathways intersect with each other at different reaction pH’s.

Aryl diazonium cations are versatile bioconjugation reagents due to their reactivity towards electron‐rich aryl residues and secondary amines, but historically their usage has been hampered by both their short lifespan in aqueous solution and the harsh conditions required to generate them in situ. Triazabutadienes address many of these issues as they are stable enough to endure multiple‐step chemical syntheses and can persist for several hours in aqueous solution, yet upon UV‐exposure rapidly release aryl diazonium cations under biologically‐relevant conditions. This paper describes the synthesis of a novel maleimide‐functionalized triazabutadiene suitable for site‐selectively installing aryl diazonium cations into proteins at neutral pH; we show reaction with this molecule and a surface‐cysteine of a thiol disulfide oxidoreductase. Through photoactivation of the site‐selectively installed triazabutadiene motifs, we generate aryl diazonium functionality, which we further derivatize via azo‐bond formation to electron‐rich aryl species, showcasing the potential utility of this strategy for the generation of photoswitches or protein‐drug conjugates.

We present catalyst-free “green” site-selective protein bioconjugations that utilise aldol condensations and are compatible with click chemistries, and construct a nanobody-derived bioconjugate capable of selectively labelling prostate cancer cells.