Emergent resistance to all clinical antibiotics calls for the next generation of therapeutics. Here we report an effective antimicrobial strategy targeting the bacterial hydrogen sulfide (H2S)–mediated defense system. We identified cystathionine γ-lyase (CSE) as the primary generator of H2S in two major human pathogens, Staphylococcus aureus and Pseudomonas aeruginosa, and discovered small molecules that inhibit bacterial CSE. These inhibitors potentiate bactericidal antibiotics against both pathogens in vitro and in mouse models of infection. CSE inhibitors also suppress bacterial tolerance, disrupting biofilm formation and substantially reducing the number of persister bacteria that survive antibiotic treatment. Our results establish bacterial H2S as a multifunctional defense factor and CSE as a drug target for versatile antibiotic enhancers.

Exquisite recognition and folding properties have rendered nucleic acids as useful supramolecular synthons for the construction of programmable architectures. Despite their proven applications in nanotechnology, scalability and fabrication of nucleic acid nanostructures still remain a challenge. Here, we describe a novel design strategy to construct new supramolecular nucleolipid synthons by using environmentally-sensitive fluorescent nucleoside analogs, based on 5-(benzofuran-2-yl)uracil and 5-(benzo[b]thiophen-2-yl)uracil cores, as the head group and fatty acids, attached to the ribose sugar, as the lipophilic group. These modified nucleoside-lipid hybrids formed organogels driven by hierarchical structures such as fibers, twisted ribbons, helical ribbons and nanotubes, which depended on the nature of fatty acid chain and nucleobase modification. NMR, single crystal X-ray and powder X-ray diffraction studies revealed the coordinated interplay of various non-covalent interactions invoked by modified nucleobase, sugar and fatty acid chains in setting up the pathway for the gelation process. Importantly, these nucleolipid gels retained or displayed aggregation-induced enhanced emission and their gelation behavior and photophysical properties could be reversibly switched by external stimuli such as temperature, ultrasound and chemicals. Furthermore, the switchable nature of nucleolipid gels to chemical stimuli enabled the selective two channel recognition of fluoride and Hg(2+) ions through visual phase transition and fluorescence change. Fluorescent organogels exhibiting such a combination of useful features is rare, and hence, we expect that this innovative design of fluorescent nucleolipid supramolecular synthons could lead to the emergence of a new family of smart optical materials and probes.

Supramolecular synthons based on nucleic acid components, nucleobases and nucleosides, and their derivatives have been highly useful in constructing wide varieties of nanoarchitectures. While most of the design strategies have focused on developing biocompatible delivery vehicles, the potential of nucleoside hybrids in assembling smart materials with tunable and sensing properties, though challenging, is gaining significant attention. Here, we describe the development of novel functional materials with surface tunability and metal-ion responsiveness by using simple nucleolipid supramolecular synthons derived by attaching various fatty acids to the 3'-O or 3',5'-O positions of the sugar residue of thymidine nucleoside. 3',5'-O-Difatty acid-substituted thymidines formed typical organogels in pure organic solvents, whereas, 3'-O-monofatty acid-substituted thymidine nucleolipids formed water-induced gels. A detailed morphological and structural analysis using microscopy, single-crystal and powder X-ray diffraction, and NMR techniques clearly revealed the molecular interactions invoked by nucleobase, sugar, fatty acid chain, and water in setting up the path for hierarchical self-assembly and gelation of thymidine nucleolipids. Interestingly, the surface property of the xerogel film fabricated using 3'-O-monosubstituted nucleolipid gels could be switched from highly hydrophobic to hydrophilic and vice versa depending on the nature of the organic solvent-water mixture used in the gelation process. On the contrary, the gelation process of disubstituted thymidine nucleolipids was highly sensitive to the presence of Hg ions as the metal ion formed a T-Hg-T base pair, thereby disrupting the H-bonding interactions that favored the gelation. Taken together, straightforward synthesis and modification-dependent gelation behavior, surface tunability, and metal-ion responsiveness underscore the potential of these supramolecular nucleolipid synthons in constructing novel functional materials.

Comprehensive understanding of the structure–function relationship of RNA both in real time and at atomic level will have a profound impact in advancing our understanding of RNA functions in biology. Here, we describe the first example of a multifunctional nucleoside probe, containing a conformation‐sensitive fluorophore and an anomalous X‐ray diffraction label (5‐selenophene uracil), which enables the correlation of RNA conformation and recognition under equilibrium and in 3D. The probe incorporated into the bacterial ribosomal RNA decoding site, fluorescently reports antibiotic binding and provides diffraction information in determining the structure without distorting native RNA fold. Further, by comparing solution binding data and crystal structure, we gained insight on how the probe senses ligand‐induced conformational change in RNA. Taken together, our nucleoside probe represents a new class of biophysical tool that would complement available tools for functional RNA investigations.

Significance RNA molecules encode proteins and play numerous regulatory roles in cells. Targeting RNA with small molecules, as is routine with proteins, would create broad opportunities for modulating biology and creating new drugs. However, this opportunity has been difficult to realize because creating novel small molecules that bind RNA, especially using modest resources, is challenging. This study integrates two widely used technologies, SHAPE chemical probing of RNA and fragment-based ligand discovery, to craft an innovative strategy for creating small molecules that bind to and modulate the activity of a structured RNA. The anticipated impact is high because the methods are simple, can be implemented in diverse research and discovery contexts, and lead to realistic druglike molecules.