With over 78 million new infections globally each year, gonorrhea remains a frustratingly common infection. Continuous development and spread of antimicrobial-resistant strains of Neisseria gonorrhoeae, the causative agent of gonorrhea, have posed a serious threat to public health. One of the mechanisms in N. gonorrhoeae involved in resistance to multiple drugs is performed by the MtrD multidrug resistance efflux pump. This study demonstrated that the MtrD pump has a broader substrate specificity than previously proposed and identified a cluster of residues important for drug binding and translocation. Additionally, a permeation pathway for the MtrD substrate progesterone actively moving through the protein was determined, revealing key interactions within the putative MtrD drug binding pockets. Identification of functionally important residues and substrate-protein interactions of the MtrD protein is crucial to develop future strategies for the treatment of multidrug-resistant gonorrhea.

Enzymes, as nature’s catalysts, speed up the very reactions that make life possible. Hydrolytic enzymes are a particularly important enzyme class responsible for the catalytic breakdown of lipids, starches, and proteins in nature, and they are displaying increasing industrial relevance. While the unrivalled catalytic effect of enzymes continues to be unmatched by synthetic systems, recent progress has been made in the design of hydrolase-inspired catalysts by imitating and incorporating specific features observed in native enzyme protein structures. The development of such enzyme-inspired materials holds promise for more robust and industrially relevant alternatives to enzymatic catalysis, as well as deeper insights into the function of native enzymes. This Review will explore recent research in the development of synthetic catalysts based on the chemistry of hydrolytic enzymes. A focus on the key aspects of hydrolytic enzyme structure and catalytic mechanism will be exploredincluding active-site chemistry, tuning transition-state interactions, and establishing reactive nanoenvironments conducive to attracting, binding, and releasing target molecules. A key focus is to highlight the progress toward an effective, versatile hydrolase-inspired catalyst by incorporating the molecular design principles laid down by nature.

Oriented electrostatic fields can exert catalytic effects upon both the kinetics and thermodynamics of chemical reactions; however, the vast majority of studies thus far have focused upon ground state chemistry and rarely consider any more than a single class of reaction. In the present study, we first use density functional theory (DFT) calculations to clarify the mechanism of CO2 storage via photochemical carboxylation of o-alkylphenyl ketones, originally proposed by Murakami et al. (J. Am. Chem. Soc. 2015, 137, 14063); we then demonstrate that oriented internal electrostatic fields arising from remote charged functional groups (CFGs) can selectively and cooperatively promote both ground-and excited-state chemical reactivity at all points along the revised mechanism, in a manner otherwise difficult to access via classical substituent effects. What is particularly striking is that electrostatic field effects upon key photochemical transitions are predictably enhanced in increasingly polar solvent, thus overcoming a central limitation of the electrostatic catalysis paradigm. We explain these observations, which should be readily extendable to the ground state.

Density functional theory calculations at the SMD/M06-2X/6-31+G­(d,p)//M06-2X/6-31G­(d) level of theory have been used to computationally design and test a pH-switchable electrostatic organocatalyst for Diels–Alder reactions. The successful catalyst design, bis­(3-(3-phenylureido)­benzyl)­ammonium, was studied for the reaction of p-quinone with range of cyclic, heterocyclic, and acyclc dienes and also the reaction of cyclopentadiene with maleimide and N-phenylmaleimide. All reactions showed significant enhancements in catalysis (10–32 kJ mol–1 in barrier lowering) when the catalyst was protonated, consistent with electrostatic stabilization of the transition state. Electrostatic effects were found to diminish in polar solvents but were predicted to remain significant in nonpolar solvents.