Oral Tebipenem Pivoxil Hydrobromide in Complicated Urinary Tract Infection.

BACKGROUND: There is a need for oral antibiotic agents that are effective against multidrug-resistant gram-negative uropathogens. Tebipenem pivoxil hydrobromide is an orally bioavailable carbapenem with activity against uropathogenic Enterobacterales, including extended-spectrum beta-lactamase-producing and fluoroquinolone-resistant strains. METHODS: In this phase 3, international, double-blind, double-dummy trial, we evaluated the efficacy and safety of orally administered tebipenem pivoxil hydrobromide as compared with intravenous ertapenem in patients with complicated urinary tract infection or acute pyelonephritis. Patients were randomly assigned, in a 1:1 ratio, to receive oral tebipenem pivoxil hydrobromide (at a dose of 600 mg every 8 hours) or intravenous ertapenem (at a dose of 1 g every 24 hours) for 7 to 10 days (or up to 14 days in patients with bacteremia). The primary efficacy end point was overall response (a composite of clinical cure and favorable microbiologic response) at a test-of-cure visit (on day 19, within a ±2-day window) in the microbiologic intention-to-treat population. The noninferiority margin was 12.5%. RESULTS: A total of 1372 hospitalized adult patients were enrolled; 868 patients (63.3%) were included in the microbiologic intention-to-treat population (50.8% of whom had complicated urinary tract infections and 49.2% of whom had pyelonephritis). An overall response was seen in 264 of 449 patients (58.8%) who received tebipenem pivoxil hydrobromide, as compared with 258 of 419 patients (61.6%) who received ertapenem (weighted difference, -3.3 percentage points; 95% confidence interval [CI], -9.7 to 3.2). Clinical cure at the test-of-cure visit was observed in 93.1% of the patients in the microbiologic intention-to-treat population who received tebipenem pivoxil hydrobromide and 93.6% of patients who received ertapenem (weighted difference, -0.6 percentage point; 95% CI, -4.0 to 2.8); the majority of patients with microbiologic response failures at the test-of-cure visit were asymptomatic patients with recurrent bacteriuria. Secondary and subgroup analyses were supportive of the primary analysis. Adverse events were observed in 25.7% of patients who received tebipenem pivoxil hydrobromide and in 25.6% of patients who received ertapenem; the most common adverse events were mild diarrhea and headache. CONCLUSIONS: Oral tebipenem pivoxil hydrobromide was noninferior to intravenous ertapenem in the treatment of complicated urinary tract infection and acute pyelonephritis and had a similar safety profile. (Funded by Spero Therapeutics and the Department of Health and Human Services; ADAPT-PO ClinicalTrials.gov number, NCT03788967.).

Breaking a Molecular Scaling Relationship Using an Iron-Iron Fused Porphyrin Electrocatalyst for Oxygen Reduction.

The design of efficient electrocatalysts is limited by scaling relationships governing trade-offs between thermodynamic and kinetic performance metrics. This ″iron law″ of electrocatalysis arises from synthetic design strategies, where structural alterations to a catalyst must balance nucleophilic versus electrophilic character. Efforts to circumvent this fundamental impasse have focused on bioinspired applications of extended coordination spheres and charged sites proximal to a catalytic center. Herein, we report evidence for breaking a molecular scaling relationship involving electrocatalysis of the oxygen reduction reaction (ORR) by leveraging ligand design. We achieve this using a binuclear catalyst (a diiron porphyrin), featuring a macrocyclic ligand with extended electronic conjugation. This ligand motif delocalizes electrons across the molecular scaffold, improving the catalyst's nucleophilic and electrophilic character. As a result, our binuclear catalyst exhibits low overpotential and high catalytic turnover frequency, breaking the traditional trade-off between these two metrics.

Thrombophilia Screening: Not So Straightforward.

Although inherited thrombophilias are lifelong risk factors for a first thrombotic episode, progression to thrombosis is multifactorial and not all individuals with inherited thrombophilia develop thrombosis in their lifetimes. Consequently, indiscriminate screening in patients with idiopathic thrombosis is not recommended, since presence of a thrombophilia does not necessarily predict recurrence or influence management, and testing should be selective. It follows that a decision to undertake laboratory detection of thrombophilia should be aligned with a concerted effort to identify any significant abnormalities, because it will inform patient management. Deficiencies of antithrombin and protein C are rare and usually determined using phenotypic assays assessing biological activities, whereas protein S deficiency (also rare) is commonly detected with antigenic assays for the free form of protein S since available activity assays are considered to lack specificity. In each case, no single phenotypic assay is capable of detecting every deficiency, because the various mutations express different molecular characteristics, rendering thrombophilia screening repertoires employing one assay per potential deficiency, of limited effectiveness. Activated protein C resistance (APCR) is more common than discrete deficiencies of antithrombin, protein C, and protein S and also often detected initially with phenotypic assays; however, some centres perform only genetic analysis for factor V Leiden, as this is responsible for most cases of hereditary APCR, accepting that acquired APCR and rare F5 mutations conferring APCR will go undetected if only factor V Leiden is evaluated. All phenotypic assays have interferences and limitations, which must be factored into decisions about if, and when, to test, and be given consideration in the laboratory during assay performance and interpretation. This review looks in detail at performance and limitations of routine phenotypic thrombophilia assays.

Impact of antibiotic pharmacokinetics in urine on recurrent bacteriuria following treatment of complicated urinary tract infections.

The clinical relevance of bacteriuria following antibiotic treatment of complicated urinary tract infections in clinical trials remains controversial. We evaluated the impact of urine pharmacokinetics on the timing of recurrent bacteriuria in a recently completed trial that compared oral tebipenem pivoxil hydrobromide to intravenous ertapenem. The urinary clearance and urine dwell time of ertapenem were prolonged relative to tebipenem and were associated with a temporal difference in the repopulation of bladder urine with bacteria following treatment, potentially confounding the assessment of efficacy.

Activated Partial Thromboplastin Time and Prothrombin Time Mixing Studies: Current State of the Art.

Mixing studies have long been in the clinical laboratory armamentarium for investigating unexpected, prolonged activated partial thromboplastin time (aPTT) or prothrombin time (PT). The purpose of the mixing study is to identify whether the aPTT/PT prolongation is secondary to a factor deficiency versus an inhibitor, which would present as a "corrected" and "noncorrected" mixing study, respectively. The differentiation between a factor deficiency and inhibitor may likely further direct clinical decisions, including additional diagnostic testing or factor replacement therapy. While aPTT/PT mixing studies are simple tests to perform, there is a lack of standardization for both the testing protocol and the interpretation of what is considered to be a corrected or noncorrected mixing study result. This review will describe the common indications for the mixing test, preanalytic variables that may affect mixing study performance, and describe several methods for interpreting the results of aPTT and PT mixing tests.

Managing the Redox Potential of PCET in Grotthuss-Type Proton Wires.

Expanding proton-coupled electron transfer to multiproton translocations (MPCET) provides a bioinspired mechanism to transport protons away from the redox site. This expansion has been accomplished by separating the initial phenolic proton donor from the pyridine-based terminal proton acceptor by a Grotthuss-type proton wire made up of concatenated benzimidazoles that form a hydrogen-bonded network. However, it was found that the midpoint potential of the phenol oxidation that launched the Grotthuss-type proton translocations is a function of the number of benzimidazoles in the hydrogen-bonded network; it becomes less positive (i.e., a weaker oxidant) as the number of bridging benzimidazoles increases. Herein, we report a strategy to maintain the high redox potential necessary for oxidative processes relevant to artificial photosynthesis, e.g., water oxidation and long-range MPCET processes for managing protons. The integrated structural and functional roles of the benzimidazole-based bridge provide sites for substitution of the benzimidazoles with electron-withdrawing groups (e.g., trifluoromethyl groups). Such substitution increases the midpoint potential of the phenoxyl radical/phenol couple so that proton translocations over ∼11 Å become thermodynamically comparable to that of an unsubstituted system where one proton is transferred over ∼2.5 Å. The extended, substituted system maintains the hydrogen-bonded network; infrared spectroelectrochemistry confirms reversible proton translocations from the phenol to the pyridyl terminal proton acceptor upon oxidation and reduction. Theory supports the change in driving force with added electron-withdrawing groups and provides insight into the role of electron density and electrostatic potential in MPCET processes associated with these Grotthuss-type proton translocations.

Testing for Lupus Anticoagulants.

Lupus anticoagulant (LA) is one of the three criteria antiphospholipid antibodies (aPLs) employed in classification, and by default diagnosis, of antiphospholipid syndrome (APS). Detection of LA is not via calibrated assays but is based on functional behavior of the antibodies in a medley of coagulation assays. A prolonged clotting time in a screening test is followed by demonstration of phospholipid dependence and inhibitory properties in confirmatory and mixing tests, respectively, which are modifications of the parent screening test. Complications arise because no single screening test is sensitive to every LA, and no test is specific for LA, because they are prone to interference by other causes of elevated clotting times. Several screening tests are available but the pairing of dilute Russell's viper venom time (dRVVT) with LA-sensitive activated partial thromboplastin time (aPTT) is widely used and recommended because it is proven to have good detection rates. Nonetheless, judicious use of other assays can improve diagnostic performance, such as dilute prothrombin time to find LA unreactive with dRVVT and aPTT, and the recently validated Taipan snake venom time with ecarin time confirmatory test that are unaffected by vitamin K antagonist and direct factor Xa inhibitor anticoagulation. Expert body guidelines and their updates have improved harmonization of laboratory practices, although some issues continue to attract debate, such as the place of mixing tests in the medley hierarchy, and areas of data manipulation such as assay cut-offs and ratio generation. This article reviews current practices and challenges in the laboratory detection of LA.

Snake Venoms in Diagnostic Hemostasis and Thrombosis.

Snake venoms have evolved primarily to immobilize and kill prey, and consequently, they contain some of the most potent natural toxins. Part of that armory is a range of hemotoxic components that affect every area of hemostasis, which we have harnessed to great effect in the study and diagnosis of hemostatic disorders. The most widely used are those that affect coagulation, such as thrombin-like enzymes unaffected by heparin and direct thrombin inhibitors, which can help confirm or dispute their presence in plasma. The liquid gold of coagulation activators is Russell's viper venom, since it contains activators of factor X and factor V. It is used in a range of clotting-based assays, such as assessment of factor X and factor V deficiencies, protein C and protein S deficiencies, activated protein C resistance, and probably the most important test for lupus anticoagulants, the dilute Russell's viper venom time. Activators of prothrombin, such as oscutarin C from Coastal Taipan venom and ecarin from saw-scaled viper venom, are employed in prothrombin activity assays and lupus anticoagulant detection, and ecarin has a valuable role in quantitative assays of direct thrombin inhibitors. Snake venoms affecting primary hemostasis include botrocetin from the jararaca, which can be used to assay von Willebrand factor activity, and convulxin from the cascavel, which can be used to detect deficiency of the platelet collagen receptor, glycoprotein VI. This article takes the reader to every area of the diagnostic hemostasis laboratory to appreciate the myriad applications of snake venoms available in diagnostic practice.

Photoelectrochemistry of metalloporphyrin-modified GaP semiconductors.

Photoelectrosynthetic materials provide a bioinspired approach for using the power of the sun to produce fuels and other value-added chemical products. However, there remains an incomplete understanding of the operating principles governing their performance and thereby effective methods for their assembly. Herein we report the application of metalloporphyrins, several of which are known to catalyze the hydrogen evolution reaction, in forming surface coatings to assemble hybrid photoelectrosynthetic materials featuring an underlying gallium phosphide (GaP) semiconductor as a light capture and conversion component. The metalloporphyrin reagents used in this work contain a 4-vinylphenyl surface-attachment group at the ß-position of the porphyrin ring and a first-row transition metal ion (Fe, Co, Ni, Cu, or Zn) coordinated at the core of the macrocycle. In addition to describing the synthesis, optical, and electrochemical properties of the homogeneous porphyrin complexes, we also report on the photoelectrochemistry of the heterogeneous metalloporphyrin-modified GaP semiconductor electrodes. These hybrid, heterogeneous-homogeneous electrodes are prepared via UV-induced grafting of the homogeneous metalloporphyrin reagents onto the heterogeneous gallium phosphide surfaces. Three-electrode voltammetry measurements performed under controlled lighting conditions enable determination of the open-circuit photovoltages, fill factors, and overall current-voltage responses associated with these composite materials, setting the stage for better understanding charge-transfer and carrier-recombination kinetics at semiconductor|catalyst|liquid interfaces.

Statewide trends and factors associated with genetic testing for hereditary cancer risk in Arkansas 2013-2018.

BACKGROUND: Early identification of hereditary cancer risk would save lives, but genetic testing (GT) has been inadequate. We assessed i) trends for hereditary breast and ovarian cancer (HBOC), Lynch syndrome, and other GT and ii) factors associated with receipt of GT. METHODS: We used data from the Arkansas All-Payer Claims Database from January 2013 through June 2018 (commercial, Medicaid), December 2017 (state employee), or December 2016 (Medicare) and identified enrollees with ≥1 month of enrollment. Using Current Procedural Terminology (CPT-4) codes, rates for GT were calculated per 100,000 person-quarters and time series regressions estimated. Second, GT and covariate information for enrollees with 24 months of continuous enrollment were used to estimate separate logistic regression models for each GT category. RESULTS: Among 2,520,575 unique enrollees, HBOC testing rates were 2.2 (Medicaid), 22.0 (commercial), 40.4 (state employee), and 13.1(Medicare) per 100,000 person-quarters and increased linearly across all plans. Older age (OR=1.24; 95%CI 1.20 - 1.28), female sex (OR=18.91; 95%CI 13.01 - 28.86), higher comorbidity burden (OR=1.08; 95%CI 1.05 - 1.12), mental disorders (OR=1.53; 95%CI 1.15 - 2.00), and state employee coverage (OR=1.65; 95%CI 1.37 - 1.97) were positively associated with HBOC testing. Less than 1 of 10,000 enrollees received Lynch syndrome testing, while < 5 of 10,000 received HBOC testing. CONCLUSION: GT rates for hereditary cancer syndromes have increased in Arkansas but remain low. Receipt of GT was explained with high discrimination by sex and plan type. IMPACT: Expansion of GT for hereditary cancer risk in Arkansas is needed to identify high-risk individuals who could benefit from risk-reduction strategies.

Electron-Nuclear Dynamics Accompanying Proton-Coupled Electron Transfer.

Although photoinduced proton-coupled electron transfer (PCET) plays an essential role in photosynthesis, a full understanding of the mechanism is still lacking due to the complex nonequilibrium dynamics arising from the strongly coupled electronic and nuclear degrees of freedom. Here we report the photoinduced PCET dynamics of a biomimetic model system investigated by means of transient IR and two-dimensional electronic-vibrational (2DEV) spectroscopies, IR spectroelectrochemistry (IRSEC), and calculations utilizing long-range-corrected hybrid density functionals. This collective experimental and theoretical effort provides a nuanced picture of the complicated dynamics and synergistic motions involved in photoinduced PCET. In particular, the evolution of the 2DEV line shape, which is highly sensitive to the mixing of vibronic states, is interpreted by accurate computational modeling of the charge separated state and is shown to represent a gradual change in electron density distribution associated with a dihedral twist that occurs on a 120 fs time scale.

A year-long extended release nanoformulated cabotegravir prodrug.

Long-acting cabotegravir (CAB) extends antiretroviral drug administration from daily to monthly. However, dosing volumes, injection site reactions and health-care oversight are obstacles towards a broad usage. The creation of poloxamer-coated hydrophobic and lipophilic CAB prodrugs with controlled hydrolysis and tissue penetrance can overcome these obstacles. To such ends, fatty acid ester CAB nanocrystal prodrugs with 14, 18 and 22 added carbon chains were encased in biocompatible surfactants named NMCAB, NM2CAB and NM3CAB and tested for drug release, activation, cytotoxicity, antiretroviral activities, pharmacokinetics and biodistribution. Pharmacokinetics studies, performed in mice and rhesus macaques, with the lead 18-carbon ester chain NM2CAB, showed plasma CAB levels above the protein-adjusted 90% inhibitory concentration for up to a year. NM2CAB, compared with NMCAB and NM3CAB, demonstrated a prolonged drug release, plasma circulation time and tissue drug concentrations after a single 45 mg per kg body weight intramuscular injection. These prodrug modifications could substantially improve CAB's effectiveness.

Clinical Validation of an Automated Fluorogenic Factor XIII Activity Assay Based on Isopeptidase Activity.

Hereditary factor XIII (FXIII) deficiency is a rare autosomal bleeding disorder which can cause life-threatening bleeding. Acquired deficiency can be immune-mediated or due to increased consumption or reduced synthesis. The most commonly used screening test is insensitive, and widely used quantitative assays have analytical limitations. The present study sought to validate Technofluor FXIII Activity, the first isopeptidase-based assay available on a routine coagulation analyser, the Ceveron s100. Linearity was evidenced throughout the measuring range, with correlation coefficients of >0.99, and coefficients of variation for repeatability and reproducibility were <5% and <10%, respectively. A normally distributed reference range of 47.0-135.5 IU/dL was derived from 154 normal donors. Clinical samples with Technofluor FXIII Activity results between 0 and 167.0 IU/dL were assayed with Berichrom® FXIII Activity, a functional ammonia release assay, and the HemosIL™ FXIII antigen assay, generating correlations of 0.950 and 0.980, respectively. Experiments with a transglutaminase inhibitor showed that Technofluor FXIII Activity can detect inhibition of enzymatic activity. No interference was exhibited by high levels of haemolysis and lipaemia, and interference by bilirubin was evident at 18 mg/dL, a level commensurate with severe liver disease. Technofluor FXIII Activity is a rapid, accurate and precise assay suitable for routine diagnostic use with fewer interferents than ammonia release FXIII activity assays.

Role of Intact Hydrogen-Bond Networks in Multiproton-Coupled Electron Transfer.

The essential role of a well-defined hydrogen-bond network in achieving chemically reversible multiproton translocations triggered by one-electron electrochemical oxidation/reduction is investigated by using pyridylbenzimidazole-phenol models. The two molecular architectures designed for these studies differ with respect to the position of the N atom on the pyridyl ring. In one of the structures, a hydrogen-bond network extends uninterrupted across the molecule from the phenol to the pyridyl group. Experimental and theoretical evidence indicates that an overall chemically reversible two-proton-coupled electron-transfer process (E2PT) takes place upon electrochemical oxidation of the phenol. This E2PT process yields the pyridinium cation and is observed regardless of the cyclic voltammogram scan rate. In contrast, when the hydrogen-bond network is disrupted, as seen in the isomer, at high scan rates (∼1000 mV s-1) a chemically reversible process is observed with an E1/2 characteristic of a one-proton-coupled electron-transfer process (E1PT). At slow cyclic voltammetric scan rates (<1000 mV s-1) oxidation of the phenol results in an overall chemically irreversible two-proton-coupled electron-transfer process in which the second proton-transfer step yields the pyridinium cation detected by infrared spectroelectrochemistry. In this case, we postulate an initial intramolecular proton-coupled electron-transfer step yielding the E1PT product followed by a slow, likely intermolecular chemical step involving a second proton transfer to give the E2PT product. Insights into the electrochemical behavior of these systems are provided by theoretical calculations of the electrostatic potentials and electric fields at the site of the transferring protons for the forward and reverse processes. This work addresses a fundamental design principle for constructing molecular wires where protons are translocated over varied distances by a Grotthuss-type mechanism.

Alternative assays to dRVVT and aPTT for lupus anticoagulant detection.

Lupus anticoagulants (LA) are heterogeneous antibodies and no single assay will detect every LA. Consequently, testing is commonly undertaken with both dilute Russell's viper venom time (dRVVT) and LA-responsive activated partial thromboplastin time (aPTT) to maximize detection rates. Although a huge body of evidence attests to the diagnostic utility of these assays, they have limitations that can render them unreliable in certain circumstances. Other assays are available for detecting LA but unfamiliarity, variable availability and technical concerns expressed in guidelines contribute to less usage than dRVVT and aPTT. However, assays such as Taipan snake venom time and Textarin time are insensitive to anticoagulants that compromise dRVVT and aPTT, and assays such as dilute prothrombin time can detect LA unreactive in dRVVT and aPTT. The pros and cons of alternative assays to dRVVT and APTT for LA detection are discussed.

Mixing studies for lupus anticoagulant: mostly no, sometimes yes.

Mixing tests have long been a mainstay in the lupus anticoagulant (LA) testing armoury of screen, mix and confirm assays. If a sample with an elevated screening test does not evidence inhibition in the mixing test, the search for an LA is halted and a different diagnostic pathway embarked upon. Recent years have seen studies evidencing sometimes high frequencies of false-negative mixing tests with perhaps sinister implications for missed diagnoses and skewed patient management. Issues such as the dilution effect, between-reagent sensitivity and specificity differences, variability of normal pooled plasma (NPP) quality and suitability and interpretive inconsistencies all contribute to questioning the reliability of mixing tests and their pivotal place in the LA assay hierarchy. The advent of integrated testing, where phospholipid-dependence is demonstrated or excluded prior to any attempt to evidence inhibitory properties with a fallible analytical principle, provides an alternative path to LA detection. In the absence of other causes of elevated clotting times, LA assay screen and confirm discordance is sufficient to secure a laboratory diagnosis of the presence of an LA, leaving the mixing test in a supplementary yet valuable role when further diagnostic discrimination is required.

Interplay between Light Flux, Quantum Efficiency, and Turnover Frequency in Molecular-Modified Photoelectrosynthetic Assemblies.

We report on the interplay between light absorption, charge transfer, and catalytic activity at molecular-catalyst-modified semiconductor liquid junctions. Factors limiting the overall photoelectrosynthetic transformations are presented in terms of distinct regions of experimental polarization curves, where each region is related to the fraction of surface-immobilized catalysts present in their activated form under varying intensities of simulated solar illumination. The kinetics associated with these regions are described using steady-state or pre-equilibrium approximations yielding rate laws similar in form to those applied in studies involving classic enzymatic reactions and Michaelis-Menten-type kinetic analysis. However, in the case of photoelectrosynthetic constructs, both photons and electrons serve as reagents for producing activated catalysts. This work forges a link between kinetic models describing biological assemblies and emerging molecular-based technologies for solar energy conversion, providing a conceptual framework for extracting kinetic benchmarking parameters currently not possible to establish.

Proton-Coupled Electron Transfer Drives Long-Range Proton Translocation in Bioinspired Systems.

Proton-coupled electron transfer (PCET) combines the movement of fundamental charged species to form an essential link between electron- and proton-transport reactions in bioenergetics and catalysis in general. The length scale over which proton transport may occur within PCET processes and the thermodynamic consequences of the resulting proton chemical potential to the oxidation reaction driving these PCET processes have not been generally established. Here we report the design of bioinspired molecules that employ oxidation-reduction processes to move reversibly two, three, and four protons via a Grotthuss-type mechanism along hydrogen-bonded networks up to ∼16 Šin length. These molecules are composed of benzimidazole moieties linking a phenol to the final proton acceptor, a cyclohexylimine. Following electrochemical oxidation of the phenol, the appearance of an infrared band at 1660 cm-1 signals proton arrival at the terminal basic site. Switching the electrode potential to reducing conditions reverses the proton translocation and resets the structure to the initial species. In addition to mimicking the first step of the iconic PCET process used by the Tyrz-His190 redox relay in photosystem II to oxidize water, this work specifically addresses theoretically and experimentally the length scale over which PCET processes may occur. The thermodynamic findings from these redox-driven, bioinspired "proton wires" have implications for understanding and rationally designing pumps for the generation of proton-motive force in artificial and reengineered photosynthesis, as well as for management of proton activity around catalytic sites, including those for water oxidation and oxygen reduction.

Proton-Coupled Electron Transfer in Artificial Photosynthetic Systems.

Artificial photosynthetic constructs can in principle operate more efficiently than natural photosynthesis because they can be rationally designed to optimize solar energy conversion for meeting human demands rather than the multiple needs of an organism competing for growth and reproduction in a complex ecosystem. The artificial photosynthetic constructs described in this Account consist primarily of covalently linked synthetic chromophores, electron donors and acceptors, and proton donors and acceptors that carry out the light absorption, electron transfer, and proton-coupled electron transfer (PCET) processes characteristic of photosynthetic cells. PCET is the movement of an electron from one site to another accompanied by proton transfer. PCET and the transport of protons over tens of angstroms are important in all living cells because they are a fundamental link between redox processes and the establishment of transmembrane gradients of proton electrochemical potential, known as proton-motive force (PMF), which is the unifying concept in bioenergetics. We have chosen a benzimidazole phenol (BIP) system as a platform for the study of PCET because with appropriate substitutions it is possible to design assemblies in which one or multiple proton transfers can accompany oxidation of the phenol. In BIP, oxidation of the phenol increases its acidity by more than ten pKa units; thus, electrochemical oxidation of the phenol is associated with a proton transfer to the imidazole. This is an example of a PCET process involving transfer of one electron and one proton, known as electron-proton transfer (EPT). When the benzimidazole moiety of BIP is substituted at the 4-position with good proton acceptor groups such as aliphatic amines, experimental and theoretical results indicate that two proton transfers occur upon one-electron oxidation of the phenol. This phenomenon is described as a one-electron-two-proton transfer (E2PT) process and results in translocation of protons over ∼7 Švia a Grotthuss-type mechanism, where the protons traverse a network of internally H-bonded sites. In the case of the E2TP process involving BIP analogues with amino group substituents, the thermodynamic price paid in redox potential to move a proton to the final proton acceptor is ∼300 mV. In this example, the decrease in redox potential limits the oxidizing power of the resulting phenoxyl radical. Thus, unlike the biological counterpart, the artificial construct is thermodynamically incapable of effectively advancing the redox state of a water oxidation catalyst. The design of systems where multiple proton transfer events are coupled to an oxidation reaction while a relatively high redox potential is maintained remains an outstanding challenge. The ability to control proton transfer and activity at defined distances and times is key to achieving proton management in the vicinity of catalysts operating at low overpotential in myriad biochemically important processes. Artificial photosynthetic constructs with well-defined structures, such as the ones described in this Account, can provide the means for discovering design principles upon which efficient redox catalysts for electrolysis and fuel cells can be based.

Controlling Proton-Coupled Electron Transfer in Bioinspired Artificial Photosynthetic Relays.

Bioinspired constructs consisting of benzimidazole-phenol moieties bearing N-phenylimines as proton-accepting substituents have been designed to mimic the H-bond network associated with the TyrZ-His190 redox relay in photosystem II. These compounds provide a platform to theoretically and experimentally explore and expand proton-coupled electron transfer (PCET) processes. The models feature H-bonds between the phenol and the nitrogen at the 3-position of the benzimidazole and between the 1 H-benzimidazole proton and the imine nitrogen. Protonation of the benzimidazole and the imine can be unambiguously detected by infrared spectroelectrochemistry (IRSEC) upon oxidation of the phenol. DFT calculations and IRSEC results demonstrate that with sufficiently strong electron-donating groups at the para-position of the N-phenylimine group (e.g., -OCH3 substitution), proton transfer to the imine is exergonic upon phenol oxidation, leading to a one-electron, two-proton (E2PT) product with the imidazole acting as a proton relay. When transfer of the second proton is not sufficiently exergonic (e.g., -CN substitution), a one-electron, one-proton transfer (EPT) product is dominant. Thus, the extent of proton translocation along the H-bond network, either ∼1.6 Å or ∼6.4 Å, can be controlled through imine substitution. Moreover, the H-bond strength between the benzimidazole NH and the imine nitrogen, which is a function of their relative p Ka values, and the redox potential of the phenoxyl radical/phenol couple are linearly correlated with the Hammett constants of the substituents. In all cases, a high potential (∼1 V vs SCE) is observed for the phenoxyl radical/phenol couple. Designing and tuning redox-coupled proton wires is important for understanding bioenergetics and developing novel artificial photosynthetic systems.